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Does Adalimumab and Brigatinib interact?

•Drug A: Adalimumab •Drug B: Brigatinib •Severity: MAJOR •Description: The metabolism of Brigatinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target. The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival. Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models. Time course of Brigatinib and exposure-response studies are still unknown. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling proteins. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution at steady state is 153 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 66% of brigatinib dose is bound to plasma proteins, which gives a blood-to-plasma concentration ratio of 0.69. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of brigatinib at steady-state was 25 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Alunbrig •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brigatinib is an anaplastic lymphoma kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Brigatinib interact? Information: •Drug A: Adalimumab •Drug B: Brigatinib •Severity: MAJOR •Description: The metabolism of Brigatinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): The anaplastic lymphoma kinase positive, metastatic non-small cell lung cancer (ALK+ NSCLC), represents only 3-5% of the NSCLC cancer cases, but the ALK mutation, overexpression and presence in several oncogenic fusion proteins in solid and hematologic tumors have pointed out the importance as well as its potential as a cancer therapy target. The ALK-related cases of NSCLC are associated with the presence of the fusion gene EML4-ALK which fused the ALK protein with the echinoderm microtubule-associated protein like-4 whose original function is the correct formation of microtubules. The presence of the aberrant fusion protein results in abnormal signaling that provokes increased cell growth, proliferation and survival. Crizotinib is indicated for the treatment of such cases but the presence of ALK kinase domain mutations confer resistance to the treatment. Thus, brigatinib is indicated for the treatment of patients with ALK+ NSCLC with intolerance to Crizotinib. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brigitanib inhibits proliferation and in vitro viability of cells expressing the fusion protein EML4-ALK as well as 17 crizotinib-resistant ALK mutants. Its action is expanded to cells expressing EGFR deletions, ROS1-L2026M, FLT3-F691L and FLT3-D835Y. Brigitanib presents a dose-dependent inhibition of tumor growth, tumor burden and prolonged survival in mice EML4-ALK xenograft models. Time course of Brigatinib and exposure-response studies are still unknown. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brigitanib acts as a tyrosine kinase inhibitor with activity against multiple kinases including ALK, ROS1, insulin-like growth factor 1 receptor and against EGFR deletions and point mutations. It acts by inhibiting ALK phosphorylation and the activation of downstream signaling proteins. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Administration of brigatinib at a concentration of 90 mg generates a Cmax of 552 ng/ml and AUC of 8165 ng h/ml while the administration of 180 mg presents a Cmax of 1452 ng/ml and AUC of 20276 ng h/ml. It has a dose proportional exposure with an accumulation ratio on the range of 1.9 to 2.4. Following oral administration of brigatinib, the Tmax is presented in a range from 1 to 4 hours. Consumption of a high-fat meal compared to overnight fasting reduces Cmax by 13% without presenting an effect on AUC. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution at steady state is 153 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 66% of brigatinib dose is bound to plasma proteins, which gives a blood-to-plasma concentration ratio of 0.69. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Brigatinib is metabolized by CYP2C8 (72.4%) and CYP3A4 (27.6%) in human liver microsomes and hepatocytes. The two major metabolites generated are the N-demethylated form and the cysteine conjugated form. Oral administration of radiolabelled brigatinib showed the systemic presence of 91.5% in the unchanged form and 3.5% of the primary metabolite AP26123. The AUC of AP26123 is less than 10% of the AUC of brigatinib and presented an inhibitory effect 3 fold lower. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of brigatinib is divided in 65% in feces and 25% in urine. From the elimination in both compartments, the unchanged for of brigatinib represented 41% of the total in feces and 86% in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of brigatinib at steady-state was 25 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): After oral administration of180 mg of brigatinib, the apparent oral clearance at steady-state is 12.7 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Treatment with brigatinib generated not mutagenic chromosomal damage. Testicular toxicity, reported as lower weight of seminal vesicles and prostate gland, testicular tubular degeneration and lower weight as well as reduced size of testes with evidence of hypoespermatogenesis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Alunbrig •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brigatinib is an anaplastic lymphoma kinase inhibitor used to treat anaplastic lymphoma kinase positive metastatic non small cell lung cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Brivaracetam interact?

•Drug A: Adalimumab •Drug B: Brivaracetam •Severity: MODERATE •Description: The metabolism of Brivaracetam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Used as adjunctive therapy for partial-onset seizures in patients 16 years of age or older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brivaracetam binds SV2A with high affinity. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The precise mechanism of brivaracetam's anti-epileptogenic activity is unknown. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Nearly 100% oral bioavailability. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.5L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): <20% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by hydrolysis of the acetamide moeity to form a carboxylic acid metabolite. Another metabolite is created via oxidation of the propyl side chain by CYP2C8 as well as CYP3A4, CYP2C19, and CYP2B6. Some conjugation with glucuronic acid and taurine account for a small amount of metabolism. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): >95% excreted in urine with <10% of the parent compound unchanged. <1% excreted in feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 7-8h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): CL/F of 0.7-1.07 mL/min kg. Clearance is primarily metabolic with less than 10% of the parent drug excreted unchanged. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No carcinogenesis or fertility impairment found. Overdose is associated with somnolence and dizziness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Briviact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brivaracetam is an anticonvulsant used for the treatment of partial-onset seizures that functions by binding to synaptic vesicle glycoprotein 2A (SV2A) in the brain.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Brivaracetam interact? Information: •Drug A: Adalimumab •Drug B: Brivaracetam •Severity: MODERATE •Description: The metabolism of Brivaracetam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Used as adjunctive therapy for partial-onset seizures in patients 16 years of age or older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brivaracetam binds SV2A with high affinity. SV2A is known to play a role in epileptogenesis through modulation of synaptic GABA release. It is thought that brivaracetam exerts its anti-epileptogenic effects through its binding to SV2A. Brivaracetam is also known to inhibit Na+ channels which may also contribute to its anti-epileptogenic action. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The precise mechanism of brivaracetam's anti-epileptogenic activity is unknown. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Nearly 100% oral bioavailability. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.5L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): <20% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by hydrolysis of the acetamide moeity to form a carboxylic acid metabolite. Another metabolite is created via oxidation of the propyl side chain by CYP2C8 as well as CYP3A4, CYP2C19, and CYP2B6. Some conjugation with glucuronic acid and taurine account for a small amount of metabolism. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): >95% excreted in urine with <10% of the parent compound unchanged. <1% excreted in feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 7-8h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): CL/F of 0.7-1.07 mL/min kg. Clearance is primarily metabolic with less than 10% of the parent drug excreted unchanged. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No carcinogenesis or fertility impairment found. Overdose is associated with somnolence and dizziness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Briviact •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brivaracetam is an anticonvulsant used for the treatment of partial-onset seizures that functions by binding to synaptic vesicle glycoprotein 2A (SV2A) in the brain. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Brodalumab interact?

•Drug A: Adalimumab •Drug B: Brodalumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Brodalumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Brodalumab has been approved for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Increase in the level of IL-17 due to blocking of its receptors. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brodalumab binds with high affinity to interleukin (IL)-17 receptor A, thereby inhibiting several pro-inflammatory cytokines from the IL-17 family. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 4.62 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.223 L/day. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Siliq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brodalumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Brodalumab interact? Information: •Drug A: Adalimumab •Drug B: Brodalumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Brodalumab. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Brodalumab has been approved for the treatment of psoriasis vulgaris, psoriatic arthritis, pustular psoriasis and psoriatic erythroderma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Increase in the level of IL-17 due to blocking of its receptors. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brodalumab binds with high affinity to interleukin (IL)-17 receptor A, thereby inhibiting several pro-inflammatory cytokines from the IL-17 family. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 4.62 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.223 L/day. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Siliq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brodalumab is a monoclonal antibody used to treat moderate to severe plaque psoriasis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Brolucizumab interact?

•Drug A: Adalimumab •Drug B: Brolucizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Brolucizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Brolucizumab is a monoclonal antibody indicated to treat neovascular age related macular degeneration. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brolucizumab is a vascular endothelial growth factor (VEGF) inhibitor which reduces proliferation of endothelial cells, vascularization of the tissue, and permeability of the vasculature. It has a long duration of action as it is given monthly. Patients should be counselled regarding the risk of endophthalmitis, retinal detachment, and arterial thromboembolic events following administration of this medication. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brolucizumab is a vascular endothelial growth factor (VEGF) inhibitor which targets the major VEGF-A isoforms: VEGF 110, VEGF 121, and VEGF 165. Inhibition of these VEGF-A isoforms reduce proliferation of endothelial cells, vascularization of the tissue, and permeability of the vasculature. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): A 3mg dose of brolucizumab reaches a C max of 20.7ng/mL with a T max of 20.3h and an AUC of 2480ng*h/mL. A 6mg dose of brolucizumab reaches a C max of 77.6ng/mL with a T max of 17.4h and an AUC of 9169ng*h/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Data regarding the volume of distribution is not readily available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Monoclonal antibodies are generally not protein bound in serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Monoclonal antibodies are expected to undergo proteolysis to smaller peptides and amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Data regarding the route of elimination is not readily available. Monoclonal antibodies are generally not eliminated in the urine, and only a small amount is excreted in bile. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The systemic half life of bolucizumab is 4.4±2.0 days. The elimination half life is 108h for a 3mg dose and 103h for a 6mg dose. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Data regarding the clearance of brolucizumab is not readily available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding the toxicity of brolucizumab is not readily available. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Beovu •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brolucizumab is an anti VEGF-A monoclonal antibody indicated to treat neovascular age related macular degeneration.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Brolucizumab interact? Information: •Drug A: Adalimumab •Drug B: Brolucizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Brolucizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Brolucizumab is a monoclonal antibody indicated to treat neovascular age related macular degeneration. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brolucizumab is a vascular endothelial growth factor (VEGF) inhibitor which reduces proliferation of endothelial cells, vascularization of the tissue, and permeability of the vasculature. It has a long duration of action as it is given monthly. Patients should be counselled regarding the risk of endophthalmitis, retinal detachment, and arterial thromboembolic events following administration of this medication. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brolucizumab is a vascular endothelial growth factor (VEGF) inhibitor which targets the major VEGF-A isoforms: VEGF 110, VEGF 121, and VEGF 165. Inhibition of these VEGF-A isoforms reduce proliferation of endothelial cells, vascularization of the tissue, and permeability of the vasculature. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): A 3mg dose of brolucizumab reaches a C max of 20.7ng/mL with a T max of 20.3h and an AUC of 2480ng*h/mL. A 6mg dose of brolucizumab reaches a C max of 77.6ng/mL with a T max of 17.4h and an AUC of 9169ng*h/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Data regarding the volume of distribution is not readily available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Monoclonal antibodies are generally not protein bound in serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Monoclonal antibodies are expected to undergo proteolysis to smaller peptides and amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Data regarding the route of elimination is not readily available. Monoclonal antibodies are generally not eliminated in the urine, and only a small amount is excreted in bile. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The systemic half life of bolucizumab is 4.4±2.0 days. The elimination half life is 108h for a 3mg dose and 103h for a 6mg dose. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Data regarding the clearance of brolucizumab is not readily available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding the toxicity of brolucizumab is not readily available. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Beovu •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brolucizumab is an anti VEGF-A monoclonal antibody indicated to treat neovascular age related macular degeneration. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Bromazepam interact?

•Drug A: Adalimumab •Drug B: Bromazepam •Severity: MODERATE •Description: The metabolism of Bromazepam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well absorbed after oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 1.56 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Urine (69%), as metabolites •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 10-20 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.82 mL/min/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Bromazepam interact? Information: •Drug A: Adalimumab •Drug B: Bromazepam •Severity: MODERATE •Description: The metabolism of Bromazepam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the short-term treatment of insomnia, short-term treatment of anxiety or panic attacks, if a benzodiazepine is required, and the alleviation of the symptoms of alcohol- and opiate-withdrawal. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bromazepam is a lipophilic, long-acting benzodiazepine and with sedative, hypnotic, anxiolytic and skeletal muscle relaxant properties. It does not possess any antidepressant qualities. Bromazepam, like other benzodiazepines, presents a risk of abuse, misuse, and dependence. According to many psychiatric experts, Bromazepam has a greater abuse potential than other benzodiazepines because of fast resorption and rapid onset of action. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Bromazepam binds to the GABA-A receptor producing a conformational change and potentiating its inhibitory effects. Other neurotransmitters are not influenced. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bioavailability is 84% following oral administration. The time to peak plasma level is 1 - 4 hours. Bromazepam is generally well absorbed after oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 1.56 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatically, via oxidative pathways (via an enzyme belonging to the Cytochrome P450 family of enzymes). One of the main metabolites is 3-hydroxybromazepam. It is pharmacologically active and the half life is similar to that of the parent compound. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Urine (69%), as metabolites •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 10-20 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.82 mL/min/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Bromazepam is a short-acting benzodiazepine with intermediate onset commonly used to treat panic disorders and severe anxiety. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Bromotheophylline interact?

•Drug A: Adalimumab •Drug B: Bromotheophylline •Severity: MODERATE •Description: The serum concentration of Bromotheophylline can be decreased when it is combined with Adalimumab. •Extended Description: According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Bromotheophylline is used as a diuretic and also, in combination with Acetaminophen, it is used for the relief of temporary water weight gain, bloating, swelling and full feeling associated with the premenstrual and menstrual periods. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bromotheophylline diuretic action will produce an immediate increase in urination frequency. This effect aids in the relief of bloating and menstrual pain. This diuretic function is performed by the an increase in glomerular filtration and a potential effect in the tubular reabsorption as it is established that the administration of these agents produce a rise in the urinary concentration of sodium a chloride and thus, an increase in their rates of excretion. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Bromotheophylline is part of the group of the xanthines. As part of this group, it is thought that bromotheophylline increases the permeability of the renal tubule, increases glomerular filtration rate and inhibits the sodium reabsorption in the proximal tubule. It is thought but not confirmed that pamabrom as a mixture seems to have an additional mechanism of action in which the presence of 2-amino-2-methyl-1-propanol produces the suppression of the antidiuretic hormone in the posterior pituitary gland. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): When administered after one single oral dosage, bromotheophylline is rapidly absorbed and it reaches a maximal plasma concentration of 2.5 mg/L in 0.78 hours. The mean residence time is registered to be of 12 hours with an AUC in the first 8 hours of 27 mg.h/L. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): This pharmacokinetic property has not been determined. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This pharmacokinetic property has not been determined. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): This pharmacokinetic property has not been determined. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): This pharmacokinetic property has not been determined. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The apparent elimination half-life is registered to be 21.35 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): This pharmacokinetic property has not been determined. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): In overdose, bromotheophylline does not produce hepatic toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Pamprin Multi-symptom, Premsyn Pms •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): No summary available

According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. The severity of the interaction is moderate.

Question: Does Adalimumab and Bromotheophylline interact? Information: •Drug A: Adalimumab •Drug B: Bromotheophylline •Severity: MODERATE •Description: The serum concentration of Bromotheophylline can be decreased when it is combined with Adalimumab. •Extended Description: According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Bromotheophylline is used as a diuretic and also, in combination with Acetaminophen, it is used for the relief of temporary water weight gain, bloating, swelling and full feeling associated with the premenstrual and menstrual periods. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bromotheophylline diuretic action will produce an immediate increase in urination frequency. This effect aids in the relief of bloating and menstrual pain. This diuretic function is performed by the an increase in glomerular filtration and a potential effect in the tubular reabsorption as it is established that the administration of these agents produce a rise in the urinary concentration of sodium a chloride and thus, an increase in their rates of excretion. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Bromotheophylline is part of the group of the xanthines. As part of this group, it is thought that bromotheophylline increases the permeability of the renal tubule, increases glomerular filtration rate and inhibits the sodium reabsorption in the proximal tubule. It is thought but not confirmed that pamabrom as a mixture seems to have an additional mechanism of action in which the presence of 2-amino-2-methyl-1-propanol produces the suppression of the antidiuretic hormone in the posterior pituitary gland. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): When administered after one single oral dosage, bromotheophylline is rapidly absorbed and it reaches a maximal plasma concentration of 2.5 mg/L in 0.78 hours. The mean residence time is registered to be of 12 hours with an AUC in the first 8 hours of 27 mg.h/L. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): This pharmacokinetic property has not been determined. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This pharmacokinetic property has not been determined. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): This pharmacokinetic property has not been determined. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): This pharmacokinetic property has not been determined. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The apparent elimination half-life is registered to be 21.35 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): This pharmacokinetic property has not been determined. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): In overdose, bromotheophylline does not produce hepatic toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Pamprin Multi-symptom, Premsyn Pms •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): No summary available Output: According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. The severity of the interaction is moderate.

Does Adalimumab and Brompheniramine interact?

•Drug A: Adalimumab •Drug B: Brompheniramine •Severity: MODERATE •Description: The metabolism of Brompheniramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Antihistamines are well absorbed from the gastrointestinal tract after oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic (cytochrome P-450 system), some renal. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bromfed DM, Lodrane D, M-end PE, Mar-cof BP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromfeniramina Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Brompheniramine interact? Information: •Drug A: Adalimumab •Drug B: Brompheniramine •Severity: MODERATE •Description: The metabolism of Brompheniramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of the symptoms of the common cold and allergic rhinitis, such as runny nose, itchy eyes, watery eyes, and sneezing. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Brompheniramine is an antihistaminergic medication of the propylamine class. It is a first-generation antihistamine. In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Brompheniramine is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Brompheniramine is an antagonist of the H1 histamine receptors with moderate antimuscarinic actions, as with other common antihistamines such as diphenhydramine. Due to its anticholindergic effects, brompheniramine may cause drowsiness, sedation, dry mouth, dry throat, blurred vision, and increased heart rate. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Antihistamines are well absorbed from the gastrointestinal tract after oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic (cytochrome P-450 system), some renal. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral, rat: LD 50 = 318 mg/kg. Signs of overdose include fast or irregular heartbeat, mental or mood changes, tightness in the chest, and unusual tiredness or weakness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bromfed DM, Lodrane D, M-end PE, Mar-cof BP •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bromfeniramina Brompheniramin Bromphéniramine Brompheniramine Brompheniraminum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Brompheniramine is a histamine H1 antagonist used to treat coughs, upper respiratory symptoms, and nasal congestion associated with allergies and the common cold. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Budesonide interact?

•Drug A: Adalimumab •Drug B: Budesonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Budesonide. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a C max of 1.50±0.79ng/mL with a T max of 2-8h and an AUC of 7.33ng*hr/mL. A high fat meal increases the T max by 2.3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a C max of 0.6-1.6nmol/L with a T max of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a C max of 2.6nmol/L with a T max of 20 minutes. A 9mg oral extended release tablet reaches a C max of 1.35±0.96ng/mL with a T max of 13.3±5.9h and an AUC of 16.43±10.52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4.31ng*hr/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of budesonide is 2.2-3.9L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Budesonide is 85-90% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Budesonide has a plasma elimination half life of 2-3.6h. The terminal elimination half life in asthmatic children 4-6 years old is 2.3h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Budesonide has a plasma clearance of 0.9-1.8L/min. The 22R form has a clearance of 1.4L/min while the 22S form has a clearance of 1.0L/min. The clearance in asthmatic children 4-6 years old is 0.5L/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Budesónida Budesonide •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Budesonide interact? Information: •Drug A: Adalimumab •Drug B: Budesonide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Budesonide. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Budesonide extended-release capsules are indicated for the treatment and maintenance of mild to moderate Crohn’s disease. Various inhaled budesonide products are indicated for prophylactic therapy in asthma and to reduce exacerbations of COPD. A budesonide nasal spray is available over the counter for symptoms of hay fever and upper respiratory allergies. Extended-release capsules are indicated to induce remission of mild to moderate ulcerative colitis and a rectal foam is used for mild to moderate distal ulcerative colitis. In addition, a delayed-release capsule formulation of budesonide is indicated to reduce proteinuria in adults with IgA nephropathy at risk of rapid disease progression. Budesonide is indicated to treat eosinophilic esophagitis (EoE): For this indication, it is only approved for use in adults in Europe while it is approved for short-term use (12 weeks) in patients 11 years of age and older in the US. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Budesonide is a glucocorticoid used to treat respiratory and digestive conditions by reducing inflammation. It has a wide therapeutic index, as dosing varies highly from patient to patient. Patients should be counselled regarding the risk of hypercorticism and adrenal axis suppression. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Extended release oral capsules are 9-21% bioavailable. A 9mg dose reaches a C max of 1.50±0.79ng/mL with a T max of 2-8h and an AUC of 7.33ng*hr/mL. A high fat meal increases the T max by 2.3h but otherwise does not affect the pharmacokinetics of budesonide. 180-360µg metered inhaled doses of budesonide are 34% deposited in the lungs, 39% bioavailable, and reach a C max of 0.6-1.6nmol/L with a T max of 10 minutes. A 1mg nebulized dose is 6% bioavailable, reaching a C max of 2.6nmol/L with a T max of 20 minutes. A 9mg oral extended release tablet reaches a C max of 1.35±0.96ng/mL with a T max of 13.3±5.9h and an AUC of 16.43±10.52ng*hr/mL. Budesonide rectal foam 2mg twice daily has an AUC of 4.31ng*hr/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of budesonide is 2.2-3.9L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. Budesonide is 85-90% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Budesonide is 80-90% metabolized at first pass. Budesonide is metabolized by CYP3A to its 2 major metabolites, 6beta-hydroxybudesonide and 16alpha-hydroxyprednisolone. The glucocorticoid activity of these metabolites is negligible (<1/100) in relation to that of the parent compound. CYP3A4 is the strongest metabolizer of budesonide, followed by CYP3A5, and CYP3A7. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 60% of a budesonide dose is recovered in the urine as the major metabolites 6beta-hydroxybudesonide, 16alpha-hydroxyprednisolone, and their conjugates. No unchanged budesonide is recovered in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Budesonide has a plasma elimination half life of 2-3.6h. The terminal elimination half life in asthmatic children 4-6 years old is 2.3h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Budesonide has a plasma clearance of 0.9-1.8L/min. The 22R form has a clearance of 1.4L/min while the 22S form has a clearance of 1.0L/min. The clearance in asthmatic children 4-6 years old is 0.5L/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Acute overdose of corticosteroids is rare, however prolonged high dosing of corticosteroids can lead to hypercorticism and adrenal axis suppression. In the case of overdose, reduce the dosage of corticosteroids temporarily. A 200mg oral dose is lethal to female mice while a 400mg oral dose is lethal to male mice. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Airsupra, Breyna, Breztri, Cortiment, Entocort, Eohilia, Pulmicort, Pulmicort Turbuhaler, Rhinocort, Symbicort, Tarpeyo, Uceris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Budesónida Budesonide •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Budesonide is a corticosteroid used to treat Crohn's disease, asthma, COPD, hay fever and allergies, and ulcerative colitis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Bupivacaine interact?

•Drug A: Adalimumab •Drug B: Bupivacaine •Severity: MODERATE •Description: The metabolism of Bupivacaine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Only 6% of bupivacaine is excreted unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Bupivacaine interact? Information: •Drug A: Adalimumab •Drug B: Bupivacaine •Severity: MODERATE •Description: The metabolism of Bupivacaine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): As an implant, bupivacaine is indicated in adults for placement into the surgical site to produce postsurgical analgesia for up to 24 hours following open inguinal hernia repair. Bupivacaine, in liposome suspension, is indicated in patients aged 6 years and older for single-dose infiltration to produce postsurgical local analgesia. In adults, it is also indicated to produce regional analgesia via an interscalene brachial plexus nerve block, a sciatic nerve block in the popliteal fossa, or an adductor canal block. Bupivicaine, in combination with meloxicam, is indicated for postsurgical analgesia in adult patients for up to 72 hours following soft tissue surgical procedures, foot and ankle procedures, and other orthopedic procedures in which direct exposure to articular cartilage is avoided. Bupivacaine, alone or in combination with epinephrine, is indicated in adults for the production of local or regional anesthesia or analgesia for surgery, dental and oral surgery procedures, diagnostic and therapeutic procedures, and for obstetrical procedures. Specific concentrations and presentations are recommended for each type of block indicated to produce local or regional anesthesia or analgesia. Finally, its use is not indicated in all blocks given clinically significant risks associated with use. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bupivacaine is a widely used local anesthetic agent. Bupivacaine is often administered by spinal injection prior to total hip arthroplasty. It is also commonly injected into surgical wound sites to reduce pain for up to 20 hours after surgery. In comparison to other local anesthetics it has a long duration of action. It is also the most toxic to the heart when administered in large doses. This problem has led to the use of other long-acting local anaesthetics:ropivacaine and levobupivacaine. Levobupivacaine is a derivative, specifically an enantiomer, of bupivacaine. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias and to cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression or both. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Like lidocaine, bupivacaine is an amide local anesthetic that provides local anesthesia through blockade of nerve impulse generation and conduction. These impulses, also known as action potentials, critically depend on membrane depolarization produced by the influx of sodium ions into the neuron through voltage-gated sodium channels. Bupivacaine crosses the neuronal membrane and exerts its anesthetic action through blockade of these channels at the intracellular portion of their pore-forming transmembrane segments. The block is use-dependent, where repetitive or prolonged depolarization increases sodium channel blockade. Without sodium ions passing through the channel’s pore, bupivacaine stabilizes the membrane at rest and therefore prevents neurotransmission. In general, the progression of anesthesia is related to the diameter, myelination and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature, (3) touch, (4) proprioception, and (5) skeletal muscle tone. While it is well-established that the main action of bupivacaine is through sodium channel block, additional analgesic effects of bupivacaine are thought to potentially be due to its binding to the prostaglandin E2 receptors, subtype EP1 (PGE2EP1), which inhibits the production of prostaglandins, thereby reducing fever, inflammation, and hyperalgesia. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Systemic absorption of local anesthetics is dose- and concentration-dependendent on the total drug administered. Other factors that affect the rate of systemic absorption include the route of administration, blood flow at the administration site, and the presence or absence of epinephrine in the anesthetic solution. Bupivacaine formulated for instillation with meloxicam produced varied systemic measures following a single dose of varying strength. In patients undergoing bunionectomy, 60 mg of bupivacaine produced a C max of 54 ± 33 ng/mL, a median T max of 3 h, and an AUC ∞ of 1718 ± 1211 ng*h/mL. For a 300 mg dose used in herniorrhaphy, the corresponding values were 271 ± 147 ng/mL, 18 h, and 15,524 ± 8921 ng*h/mL. Lastly, a 400 mg dose used in total knee arthroplasty produced values of 695 ± 411 ng/mL, 21 h, and 38,173 ± 29,400 ng*h/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bupivacaine is ~95% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Amide-type local anesthetics such as bupivacaine are metabolized primarily in the liver via conjugation with glucuronic acid. The major metabolite of bupivacaine is 2,6-pipecoloxylidine, which is mainly catalyzed via cytochrome P450 3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Only 6% of bupivacaine is excreted unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 2.7 hours in adults and 8.1 hours in neonates. Bupivacaine applied together with meloxicam for postsurgical analgesia had a median half-life of 15-17 hours, depending on dose and application site. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The mean seizure dosage of bupivacaine in rhesus monkeys was found to be 4.4 mg/kg with mean arterial plasma concentration of 4.5 mcg/mL. The intravenous and subcutaneous LD 50 in mice is 6 to 8 mg/kg and 38 to 54 mg/kg respectively. Recent clinical data from patients experiencing local anesthetic induced convulsions demonstrated rapid development of hypoxia, hypercarbia, and acidosis with bupivacaine within a minute of the onset of convulsions. These observations suggest that oxygen consumption and carbon dioxide production are greatly increased during local anesthetic convulsions and emphasize the importance of immediate and effective ventilation with oxygen which may avoid cardiac arrest. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Exparel, Kenalog, Marbeta, Marcaine, Marcaine With Epinephrine, Marvona Suik, P-Care M, P-Care MG, P-care, Posimir, Readysharp Anesthetics Plus Ketorolac, Readysharp-A, Readysharp-p40, Readysharp-p80, Sensorcaine, Sensorcaine With Epinephrine, Vivacaine, Xaracoll, Zynrelef •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Bupivacaina Bupivacaine Bupivacainum DL-Bupivacaine Racemic bupivacaine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Buprenorphine interact?

•Drug A: Adalimumab •Drug B: Buprenorphine •Severity: MODERATE •Description: The metabolism of Buprenorphine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone. The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. Injections are part of a complete treatment plan that includes counselling and psychosocial support. Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.[F4718] Withdrawal Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.[F4718] Risk of Respiratory and Central Nervous System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Use buprenorphine and naloxone sublingual tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients. Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms. Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Gastrointestinal Effects Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy. Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. Orthostatic Hypotension Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients. Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i.e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0.5mg was found to be 30.75 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buprenophine Buprenorfina Buprenorphine Buprenorphinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for maintenance treatment of opioid addiction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Buprenorphine interact? Information: •Drug A: Adalimumab •Drug B: Buprenorphine •Severity: MODERATE •Description: The metabolism of Buprenorphine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Buprenorphine is available in different formulations, such as sublingual tablets, buccal films, transdermal films, and injections, alone or in combination with naloxone. The buccal film, intramuscular or intravenous injection, and transdermal formulation are indicated for the management of pain severe enough to require an opioid analgesic and for which alternate treatments are inadequate. The extended-release subcutaneous injections of buprenorphine are indicated for the treatment of moderate to severe opioid use disorder in patients who have initiated treatment with a single dose of a transmucosal buprenorphine product or who are already being treated with buprenorphine. Injections are part of a complete treatment plan that includes counselling and psychosocial support. Sublingual tablets and buccal films, in combination with naloxone, are indicated for the maintenance treatment of opioid dependence as part of a complete treatment plan that includes counselling and psychosocial support. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Buprenorphine interacts predominately with the opioid mu-receptor. These mu-binding sites are discretely distributed in the human brain, spinal cord, and other tissues. In clinical settings, buprenorphine exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. In addition to analgesia, alterations in mood, euphoria and dysphoria, and drowsiness commonly occur. Buprenorphine depresses the respiratory centers, depresses the cough reflex, and constricts the pupils. Dependence Buprenorphine is a partial agonist at the mu-opioid receptor and chronic administration produces physical dependence of the opioid type, characterized by withdrawal signs and symptoms upon abrupt discontinuation or rapid taper. The withdrawal syndrome is typically milder than seen with full agonists and may be delayed in onset. Buprenorphine can be abused in a manner similar to other opioids. This should be considered when prescribing or dispensing buprenorphine in situations when the clinician is concerned about an increased risk of misuse, abuse, or diversion.[F4718] Withdrawal Abrupt discontinuation of treatment is not recommended as it may result in an opioid withdrawal syndrome that may be delayed in onset. Signs and symptoms may include body aches, diarrhea, gooseflesh, loss of appetite, nausea, nervousness or restlessness, anxiety, runny nose, sneezing, tremors or shivering, stomach cramps, tachycardia, trouble with sleeping, unusual increase in sweating, palpitations, unexplained fever, weakness and yawning.[F4718] Risk of Respiratory and Central Nervous System (CNS) Depression and Overdose Buprenorphine has been associated with life-threatening respiratory depression and death. Many, but not all, post-marketing reports regarding coma and death involved misuse by self-injection or were associated with the concomitant use of buprenorphine and benzodiazepines or other CNS depressant, including alcohol. Use buprenorphine and naloxone sublingual tablets with caution in patients with compromised respiratory function (e.g., chronic obstructive pulmonary disease, cor pulmonale, decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression). Risk of Overdose in Opioid Naïve Patients There have been reported deaths of opioid-naïve individuals who received a 2 mg dose of buprenorphine as a sublingual tablet for analgesia. Buprenorphine and naloxone sublingual tablets are not appropriate as an analgesic in opioid-naïve patients. Precipitation of Opioid Withdrawal Signs and Symptoms If buprenorphine is started in opioid-dependent individuals, it will displace the other opioids and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms. Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Because it contains naloxone, buprenorphine and naloxone sublingual tablets are also highly likely to produce marked and intense withdrawal signs and symptoms if misused parenterally by individuals dependent on full opioid agonists such as heroin, morphine, or methadone. Gastrointestinal Effects Buprenorphine and other morphine-like opioids have been shown to decrease bowel motility and cause constipation. Buprenorphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions and should be administered with caution to patients with dysfunction of the biliary tract. Effects on the Endocrine System Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon. Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation. Adrenal Insufficiency Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure. If adrenal insufficiency is suspected, confirm the diagnosis with diagnostic testing as soon as possible. If adrenal insufficiency is diagnosed, treat with physiologic replacement doses of corticosteroids. Wean the patient off of the opioid to allow adrenal function to recover and continue corticosteroid treatment until adrenal function recovers. Other opioids may be tried as some cases reported use of a different opioid without recurrence of adrenal insufficiency. The information available does not identify any particular opioids as being more likely to be associated with adrenal insufficiency. Use in Patients With Impaired Hepatic Function Buprenorphine/naloxone products are not recommended in patients with severe hepatic impairment and may not be appropriate for patients with moderate hepatic impairment. The doses of buprenorphine and naloxone in this fixed-dose combination product cannot be individually titrated, and hepatic impairment results in a reduced clearance of naloxone to a much greater extent than buprenorphine. Therefore, patients with severe hepatic impairment will be exposed to substantially higher levels of naloxone than patients with normal hepatic function. This may result in an increased risk of precipitated withdrawal at the beginning of treatment (induction) and may interfere with buprenorphine’s efficacy throughout treatment. In patients with moderate hepatic impairment, the differential reduction of naloxone clearance compared to buprenorphine clearance is not as great as in subjects with severe hepatic impairment. However, buprenorphine/naloxone products are not recommended for initiation of (treatment induction) in patients with moderate hepatic impairment due to the increased risk of precipitated withdrawal. Buprenorphine/naloxone products may be used with caution for maintenance treatment in patients with moderate hepatic impairment who have initiated treatment on a buprenorphine product without naloxone. However, patients should be carefully monitored and consideration given to the possibility of naloxone interfering with buprenorphine’s efficacy. Risk of Hepatitis, Hepatic Events Cases of cytolytic hepatitis and hepatitis with jaundice have been observed in individuals receiving buprenorphine in clinical trials and through post-marketing adverse event reports. The spectrum of abnormalities ranges from transient asymptomatic elevations in hepatic transaminases to case reports of death, hepatic failure, hepatic necrosis, hepatorenal syndrome, and hepatic encephalopathy. In many cases, the presence of pre-existing liver enzyme abnormalities, infection with hepatitis B or hepatitis C virus, concomitant usage of other potentially hepatotoxic drugs, and ongoing injecting drug use may have played a causative or contributory role. In other cases, insufficient data were available to determine the etiology of the abnormality. Withdrawal of buprenorphine has resulted in amelioration of acute hepatitis in some cases; however, in other cases no dose reduction was necessary. The possibility exists that buprenorphine had a causative or contributory role in the development of the hepatic abnormality in some cases. Liver function tests, prior to initiation of treatment is recommended to establish a baseline. Periodic monitoring of liver function during treatment is also recommended. A biological and etiological evaluation is recommended when a hepatic event is suspected. Depending on the case, buprenorphine and naloxone sublingual tablets may need to be carefully discontinued to prevent withdrawal signs and symptoms and a return by the patient to illicit drug use, and strict monitoring of the patient should be initiated. Orthostatic Hypotension Like other opioids, buprenorphine and naloxone sublingual tablets may produce orthostatic hypotension in ambulatory patients. Elevation of Cerebrospinal Fluid Pressure Buprenorphine, like other opioids, may elevate cerebrospinal fluid pressure and should be used with caution in patients with head injury, intracranial lesions, and other circumstances when cerebrospinal pressure may be increased. Buprenorphine can produce miosis and changes in the level of consciousness that may interfere with patient evaluation. Elevation of Intracholedochal Pressure Buprenorphine has been shown to increase intracholedochal pressure, as do other opioids, and thus should be administered with caution to patients with dysfunction of the biliary tract. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Buprenorphine is a partial agonist at the mu-opioid receptor and an antagonist at the kappa-opioid receptor. It demonstrates a high affinity for the mu-opioid receptor but has lower intrinsic activity compared to other full mu-opioid agonists such as heroin, oxycodone, or methadone. This means that buprenorphine preferentially binds the opioid receptor and displaces lower affinity opioids without activating the receptor to a comparable degree. Clinically, this results in a slow onset of action and a clinical phenomenon known as the "ceiling effect" where once a certain dose is reached buprenorphine's effects plateau. This effect can be beneficial, however, as dose-related side effects such as respiratory depression, sedation, and intoxication also plateau at around 32mg, resulting in a lower risk of overdose compared to methadone and other full agonist opioids. It also means that opioid-dependent patients do not experience sedation or euphoria at the same rate that they might experience with more potent opioids, improving quality of life for patients with severe pain and reducing the reinforcing effects of opioids which can lead to drug-seeking behaviours. Buprenorphine's high affinity, but low intrinsic activity for the mu-opioid receptor also means that if it is started in opioid-dependent individuals, it will displace the other opioids without creating an equal opioid effect and cause a phenomenon known as "precipitated withdrawal" which is characterized by a rapid and intense onset of withdrawal symptoms (i.e. anxiety, restlessness, gastrointestinal distress, diaphoresis, intense drug cravings, and tachycardia). Individuals must therefore be in a state of mild to moderate withdrawal before starting therapy with buprenorphine. Buprenorphine is commercially available as the brand name product Suboxone which is formulated in a 4:1 fixed-dose combination product along with naloxone, a non-selective competitive opioid receptor antagonist. Combination of an opioid agonist with an opioid antagonist may seem counterintuitive, however this combination with naloxone is intended to reduce the abuse potential of Suboxone, as naloxone is poorly absorbed by the oral route (and has no effect when taken orally), but would reverse the opioid agonist effects of buprenorphine if injected intravenously. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bioavailablity of buprenorphine/naloxone is very high following intravenous or subcutaneous administration, lower by the sublingual or buccal route, and very low when administered by the oral route. It is therefore provided as a sublingual tablet that is absorbed from the oral mucosa directly into systemic circulation. Clinical pharmacokinetic studies found that there was wide inter-patient variability in the sublingual absorption of buprenorphine and naloxone, but within subjects the variability was low. Both Cmax and AUC of buprenorphine increased in a linear fashion with the increase in dose (in the range of 4 to 16 mg), although the increase was not directly dose-proportional. Buprenorphine combination with naloxone (2mg/0.5mg) provided in sublingual tablets demonstrated a Cmax of 0.780 ng/mL with a Tmax of 1.50 hr and AUC of 7.651 ng.hr/mL. Coadministration with naloxone does not effect the pharmacokinetics of buprenorphine. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Buprenorphine is highly lipophilic, and therefore extensively distributed, with rapid penetration through the blood-brain barrier. The estimated volume of distribution is 188 - 335 L when given intravenously. It is able to cross into the placenta and breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Buprenorphine is approximately 96% protein-bound, primarily to alpha- and beta-globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buprenorphine is metabolized to norbuprenorphine via Cytochrome P450 3A4/3A5-mediated N-dealkylation. Buprenorphine and norbuprenorphine both also undergo glucuronidation to the inactive metabolites buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, respectively. While norbuprenorphine has been found to bind to opioid receptors in-vitro, brain concentrations are very low which suggests that it does not contribute to the clinical effects of buprenorphine. Naloxone undergoes direct glucuronidation to naloxone-3-glucuronide as well as N-dealkylation, and reduction of the 6-oxo group. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Buprenorphine, like morphine and other phenolic opioid analgesics, is metabolized by the liver and its clearance is related to hepatic blood flow. It is primarily eliminated via feces (as free forms of buprenorphine and norbuprenorphine) while 10 - 30% of the dose is excreted in urine (as conjugated forms of buprenorphine and norbuprenorphine). The overall mean elimination half-life of buprenorphine in plasma ranges from 31 to 42 hours, although the levels are very low 10 hours after dosing (majority of AUC of buprenorphine is captured within 10 hours), indicating that the effective half-life may be shorter. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Buprenorphine demonstrates slow dissociation kinetics (~166 min), which contributes to its long duration of action and allows for once-daily or even every-second-day dosing. In clinical trial studies, the half-life of sublingually administered buprenorphine/naloxone 2mg/0.5mg was found to be 30.75 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Clearance may be higher in children than in adults. Plasma clearance rate, IV administration, anaesthetized patients = 901.2 ± 39.7 mL/min; Plasma clearance rate, IV administration, healthy subjects = 1042 - 1280 mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Manifestations of acute overdose include pinpoint pupils, sedation, hypotension, respiratory depression and death. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Belbuca, Brixadi, Buprenex, Buprenorphine, Butrans, Sublocade, Suboxone, Subutex, Zubsolv •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buprenophine Buprenorfina Buprenorphine Buprenorphinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Buprenorphine is a partial opioid agonist used for management of severe pain that is not responsive to alternative treatments. Also used for maintenance treatment of opioid addiction. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Bupropion interact?

•Drug A: Adalimumab •Drug B: Bupropion •Severity: MODERATE •Description: The metabolism of Bupropion can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 24 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Bupropion interact? Information: •Drug A: Adalimumab •Drug B: Bupropion •Severity: MODERATE •Description: The metabolism of Bupropion can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Bupropion is indicated for the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. When used in combination with naltrexone as the marketed product ContraveⓇ, bupropion is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of: 30 kg/m^2 or greater (obese) or 27 kg/m^2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia). Bupropion is also used off-label as a first-line treatment in patients with ADHD and comorbid bipolar disorder when used as an adjunct to mood stabilizers. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Bupropion is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitors, or other known antidepressant agents. Compared to classical tricyclic antidepressants, Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine. In addition, Bupropion does not inhibit monoamine oxidase. Bupropion has been found to be essentially inactive at the serotonin transporter (SERT)(IC50 >10 000 nM), however both bupropion and its primary metabolite hydroxybupropion have been found to block the function of cation-selective serotonin type 3A receptors (5-HT3ARs). Bupropion produces dose-related central nervous system (CNS) stimulant effects in animals, as evidenced by increased locomotor activity, increased rates of responding in various schedule-controlled operant behaviour tasks, and, at high doses, induction of mild stereotyped behaviour. Due to these stimulant effects and selective activity at dopamine and norepinephrine receptors, bupropion has been identified as having an abuse potential. Bupropion has a similar structure to the controlled substance Cathinone, and has been identified as having mild amphetamine-like activity, particularly when inhaled or injected. Bupropion is also known to lower the seizure threshold, making any pre-existing seizure conditions a contraindication to its use. This risk is exacerbated when bupropion is combined with other drugs or substances that lower the seizure threshold, such as cocaine, or in clinical situations that would increase the risk of a seizure such as abrupt alcohol or benzodiazepine withdrawal. As norepinephrine has been shown to have anticonvulsant properties, bupropion's inhibitory effects on NET are thought to contribute to its pro-convulsant activity. Bupropion has been shown to increase blood pressure and pose a risk for exacerbation of unmanaged or pre-existing hypertension, however, clinical trials of bupropion in smokers with CVD have not identified an increased incidence of CV events including stroke or heart attack. In clinical trials, the mean increase in systolic blood pressure associated with the use of bupropion was found to be 1.3 mmHg. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Bupropion is a norepinephrine/dopamine-reuptake inhibitor (NDRI) that exerts its pharmacological effects by weakly inhibiting the enzymes involved in the uptake of the neurotransmitters norepinephrine and dopamine from the synaptic cleft, therefore prolonging their duration of action within the neuronal synapse and the downstream effects of these neurotransmitters. More specifically, bupropion binds to the norepinephrine transporter (NET) and the dopamine transporter (DAT). Bupropion was originally classified as an "atypical" antidepressant because it does not exert the same effects as the classical antidepressants such as Monoamine Oxidase Inhibitors (MAOIs), Tricyclic Antidepressants (TCAs), or Selective Serotonin Reuptake Inhibitors (SSRIs). While it has comparable effectiveness to typical first-line options for the treatment of depression such as SSRIs, bupropion is a unique option for the treatment of MDD as it lacks any clinically relevant serotonergic effects, typical of other mood medications, or any effects on histamine or adrenaline receptors. Lack of activity at these receptors results in a more tolerable side effect profile; bupropion is less likely to cause sexual side effects, sedation, or weight gain as compared to SSRIs or TCAs, for example. When used as an aid to smoking cessation, bupropion is thought to confer its anti-craving and anti-withdrawal effects by inhibiting dopamine reuptake, which is thought to be involved in the reward pathways associated with nicotine, and through the antagonism of the nicotinic acetylcholinergic receptor (AChR), thereby blunting the effects of nicotine. Furthermore, the stimulatory effects produced by bupropion in the central nervous system are similar to nicotine's effects, making low doses of bupropion a suitable option as a nicotine substitute. When used in combination with naltrexone in the marketed product ContraveⓇ for chronic weight management, the two components are thought to have effects on areas of the brain involved in the regulation of food intake. This includes the hypothalamus, which is involved in appetite regulation, and the mesolimbic dopamine circuit, which is involved in reward pathways. Studies have shown that the combined activity of bupropion and naltrexone increase the firing rate of hypothalamic pro-opiomelanocortin (POMC) neurons and blockade of opioid receptor-mediated POMC auto-inhibition, which are associated with a reduction in food intake and increased energy expenditure. This combination was also found to reduce food intake when injected directly into the ventral tegmental area of the mesolimbic circuit in mice, which is an area associated with the regulation of reward pathways. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bupropion is currently available in 3 distinct, but bioequivalent formulations: immediate release (IR), sustained-release (SR), and extended-release (XL). Immediate Release Formulation In humans, following oral administration of bupropion hydrochloride tablets, peak plasma bupropion concentrations are usually achieved within 2 hours. IR formulations provide a short duration of action and are therefore generally dosed three times per day. Sustained Release Formulation In humans, following oral administration of bupropion hydrochloride sustained-release tablets (SR), peak plasma concentration (Cmax) of bupropion is usually achieved within 3 hours. SR formulations provide a 12-hour extended release of medication and are therefore generally dosed twice per day. Extended Release Formulation Following single oral administration of bupropion hydrochloride extended-release tablets (XL) to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours. The presence of food did not affect the peak concentration or area under the curve of bupropion. XL formulations provide a 24-hour extended release of medication and are therefore generally dosed once per day/ In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state Cmax for bupropion after bupropion hydrochloride sustained-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, bupropion hydrochloride sustained-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites. Furthermore, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL), 300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites (hydroxybupropion, threohydrobupropion, and erythrohydrobupropion). Additionally, in a study comparing 14-day dosing with bupropion hydrochloride extended-release tablets (XL) 300 mg once daily to the sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence was demonstrated for peak plasma concentration and area under the curve for bupropion and the three metabolites. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant. Following a single-dose administration of bupropion hydrochloride extended-release tablets (SR) in humans, Cmax of bupropion's metabolite hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (±5) hours and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half-lives are longer, 33(±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times that of bupropion, respectively. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg per mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers, threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Hydroxybupropion has been shown to have the same affinity as bupropion for the norepinephrine transporter (NET) but approximately 50% of its antidepressant activity despite reaching concentrations of ~10-fold higher than that of the parent drug. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one-half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion. Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Bupropion is extensively metabolized in humans. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of metachlorobenzoic acid, which is then excreted as the major urinary metabolite. Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 24 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include seizures, hallucinations, loss of consciousness, tachycardia, and cardiac arrest. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aplenzin, Auvelity, Budeprion, Contrave, Forfivo, Wellbutrin, Zyban •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Bupropion is a norepinephrine and dopamine reuptake inhibitor used in the treatment of major depressive disorder (MDD), seasonal affective disorder (SAD), and as an aid to smoking cessation. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Burosumab interact?

•Drug A: Adalimumab •Drug B: Burosumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Burosumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): This drug has the ability to reduce the loss of phosphate, to improve pathologically low serum phosphate concentrations and other metabolic changes, as well as to reduce the severity of rickets as seen radiographically. In summary, this drug works to support of bone mineralization. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Burosumab is a recombinant human monoclonal antibody (IgG1) that both binds to and inhibits the actions of fibroblast growth factor 23 (FGF23). By inhibiting this growth factor, burosumab increases the tubular reabsorption of phosphate from the kidney and thus increases serum concentration of 1, 25 dihydroxy-Vitamin D. This form of vitamin D enhances intestinal absorption of phosphate and calcium, supporting bone mineralization. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Burosumab absorption after subcutaneous injection sites into to the blood circulation is nearly complete. Following the subcutaneous route of administration, the time to reach maximum serum concentrations (Tmax) of burosumab is estimated at 5-10 days. The peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of serum burosumab is proportional to the dose, over the dose range of 0.1-2.0 mg/kg. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Burosumab is comprised solely of amino acids and carbohydrates as a native immunoglobulin and is not likeluy to be eliminated by hepatic metabolic mechanisms. The metabolism of burosumab and elimination are expected to follow the immunoglobulin clearance pathways, which results in its degradation to smaller peptides and amino acids. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Because of its molecular size, burosumab is not likely to be directly excreted. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): About 19 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of burosumab depends on weight and is estimated to be 0.290 L/day and 0.136 L/day in a typical adult (70 kg) and pediatric (30 kg) XLH patient, respectively. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The toxicity of Crysvita can be classified into several categories: Ectopic mineralisation: Clinically manifested by nephrocalcinosis, has been seen in patients with XLH treated with oral phosphorous and vitamin D analogues. These drugs should be stopped at least 1 week before starting burosumab treatment. Monitoring for signs and symptoms of nephrocalcinosis, e.g. by renal ultrasonography, is recommended at the beginning of treatment and at intervals of every 6 months for the first 12 months of treatment, and yearly thereafter. Regular monitoring of plasma alkaline phosphatases, Calcium, PTH, and creatinine is advised at 6 months intervals(every 3 months for children 1- 2 years) or as indicated. Monitoring of urine calcium and phosphate is suggested every 3 months. Hyperphosphatemia Fasting serum phosphate level must be followed due to the risk of hyperphosphatemia while taking this drug. To decrease the risk for ectopic mineralization, it is advised that fasting serum phosphate is aimed to be in the lower end of the normal reference range for any given age. Dose interruption and/or dose reduction may be required. Regular measurement of postprandial serum phosphate is advised. Serum parathyroid hormone increases Increases in serum parathyroid hormone have been measured in some XLH patients while undergoing treatment with burosumab. Regular measurement of serum parathyroid hormone is recommended. Injection site reactions Administration of burosumab, like other injections, can lead to local injection site reactions. Administration of this drug should cease in any patient experiencing severe injection site reactions and appropriate medical therapy administered. Hypersensitivity Burosumab should be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be provided. Reproductive toxicity/pregnancy There are no or limited amount of data available from the use of burosumab in pregnant women. Studies in animals have demonstrated reproductive toxicity. Burosumab use is not advised during pregnancy and in women of childbearing potential/age currently not using contraception. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Crysvita •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Burosumab is a fibroblast growth factor 23 blocking antibody used to treat X-linked hypophosphatemia.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Burosumab interact? Information: •Drug A: Adalimumab •Drug B: Burosumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Burosumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): This drug is indicated for the treatment of X-linked hypophosphatemia with radiological evidence of bone disease in children of 1 year of age and older and adolescents with growing skeletons. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): This drug has the ability to reduce the loss of phosphate, to improve pathologically low serum phosphate concentrations and other metabolic changes, as well as to reduce the severity of rickets as seen radiographically. In summary, this drug works to support of bone mineralization. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Burosumab is a recombinant human monoclonal antibody (IgG1) that both binds to and inhibits the actions of fibroblast growth factor 23 (FGF23). By inhibiting this growth factor, burosumab increases the tubular reabsorption of phosphate from the kidney and thus increases serum concentration of 1, 25 dihydroxy-Vitamin D. This form of vitamin D enhances intestinal absorption of phosphate and calcium, supporting bone mineralization. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Burosumab absorption after subcutaneous injection sites into to the blood circulation is nearly complete. Following the subcutaneous route of administration, the time to reach maximum serum concentrations (Tmax) of burosumab is estimated at 5-10 days. The peak serum concentration (Cmax) and area under the concentration-time curve (AUC) of serum burosumab is proportional to the dose, over the dose range of 0.1-2.0 mg/kg. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Burosumab is comprised solely of amino acids and carbohydrates as a native immunoglobulin and is not likeluy to be eliminated by hepatic metabolic mechanisms. The metabolism of burosumab and elimination are expected to follow the immunoglobulin clearance pathways, which results in its degradation to smaller peptides and amino acids. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Burosumab is composed solely of amino acids and carbohydrates as a native immunoglobulin and is unlikely to be eliminated via hepatic metabolic mechanisms. Its metabolism and elimination are expected to follow the immunoglobulin clearance pathways, resulting in degradation to small peptides and individual amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Because of its molecular size, burosumab is not likely to be directly excreted. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): About 19 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of burosumab depends on weight and is estimated to be 0.290 L/day and 0.136 L/day in a typical adult (70 kg) and pediatric (30 kg) XLH patient, respectively. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The toxicity of Crysvita can be classified into several categories: Ectopic mineralisation: Clinically manifested by nephrocalcinosis, has been seen in patients with XLH treated with oral phosphorous and vitamin D analogues. These drugs should be stopped at least 1 week before starting burosumab treatment. Monitoring for signs and symptoms of nephrocalcinosis, e.g. by renal ultrasonography, is recommended at the beginning of treatment and at intervals of every 6 months for the first 12 months of treatment, and yearly thereafter. Regular monitoring of plasma alkaline phosphatases, Calcium, PTH, and creatinine is advised at 6 months intervals(every 3 months for children 1- 2 years) or as indicated. Monitoring of urine calcium and phosphate is suggested every 3 months. Hyperphosphatemia Fasting serum phosphate level must be followed due to the risk of hyperphosphatemia while taking this drug. To decrease the risk for ectopic mineralization, it is advised that fasting serum phosphate is aimed to be in the lower end of the normal reference range for any given age. Dose interruption and/or dose reduction may be required. Regular measurement of postprandial serum phosphate is advised. Serum parathyroid hormone increases Increases in serum parathyroid hormone have been measured in some XLH patients while undergoing treatment with burosumab. Regular measurement of serum parathyroid hormone is recommended. Injection site reactions Administration of burosumab, like other injections, can lead to local injection site reactions. Administration of this drug should cease in any patient experiencing severe injection site reactions and appropriate medical therapy administered. Hypersensitivity Burosumab should be discontinued if serious hypersensitivity reactions occur and appropriate medical treatment should be provided. Reproductive toxicity/pregnancy There are no or limited amount of data available from the use of burosumab in pregnant women. Studies in animals have demonstrated reproductive toxicity. Burosumab use is not advised during pregnancy and in women of childbearing potential/age currently not using contraception. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Crysvita •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Burosumab is a fibroblast growth factor 23 blocking antibody used to treat X-linked hypophosphatemia. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Buspirone interact?

•Drug A: Adalimumab •Drug B: Buspirone •Severity: MODERATE •Description: The metabolism of Buspirone can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Buspar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buspiron Buspirona Buspirone Buspironum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Buspirone interact? Information: •Drug A: Adalimumab •Drug B: Buspirone •Severity: MODERATE •Description: The metabolism of Buspirone can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated for the management of anxiety disorders or the short-term relief of the symptoms of anxiety. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The clinical effect of buspirone in alleviating the symptoms of generalized anxiety disorders typically takes 2 to 4 weeks to achieve. The delayed onset of action of buspirone suggests that the therapeutic effectiveness in generalized anxiety may involved more than its molecular mechanism of action at the 5-HT 1A receptors, or buspirone may induce adaptations of 5-HT 1A receptors. Buspirone was not shown to alter the psychomotor or cognitive function in healthy volunteers, and the risk of developing sedation is relatively low compared to other anxiolytics, such as benzodiazepines. Unlike benzodiazepines and barbiturates used in anxiety disorders, buspirone is not associated with a risk for developing physical dependence or withdrawal, or any significant interaction with central nervous system depressants such as ethanol. This is due to the lack of effects on GABA receptors. Buspirone also does not exhibit any anticonvulsant or muscle-relaxing properties, but may interfere with arousal reactions due to its inhibitory action on the aactivity of noradrenergic locus coerulus neurons. Despite its clinical effectiveness in generalized anxiety, buspirone demonstrated limited clinical effectiveness on panic disorders, severe anxiety, phobias, and obsessive compulsive disorders. The clinical effectiveness of the long-term use of buspirone, for more than 3 to 4 weeks, has not demonstrated in controlled trials but there were no observable significant adverse events in patients receiving buspirone for a year in a study of long-term use. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The therapeutic action of buspirone in generalized anxiety disorders is thought to be mainly derived from its interaction with two major 5-HT 1A receptor subtypes that are involved in the brain's anxiety and fear circuitry to enhance the serotonergic activity in these brain areas. Buspirone acts as a full agonist at presynaptic 5-HT 1A receptors, or 5-HT 1A autoreceptors, expressed at dorsal raphe while acting as a partial agonist at the postsynaptic 5-HT 1A receptors expressed on hippocampus and cortex. 5-HT 1A receptors function as inhibitory autoreceptors by being expressed on the soma or dendrites of serotonergic neurons or mediate postsynaptic actions of 5-HT by being highly expressed on the corticolimbic circuits. They are inhibitory G-protein coupled receptors that couple to Gi/Go proteins. When activated, presynaptic 5-HT 1A autoreceptors causes neuron hyperpolarization and reduces the firing rate of the serotonergic neuron, thereby decreasing extracellular 5-HT levels in the neuron's projection areas. Activated postsynaptic 5-HT 1A receptors promote hyperpolarization to released 5-HT on pyramidal neurons. The anxiolytic action of buspirone is mainly thought to arise from the interaction at presynaptic 5-HT 1A autoreceptors. Acting as a potent agonist in these receptors, buspirone initially causes activation of these autoreceptors and inhibition of 5-HT release. It is proposed that buspirone induces desensitization of somatodendritic autoreceptors over time, which may explain the delayed onset of action of the drug. Desensitization of the autoreceptors ultimately results in heightened excitation of serotonergic neurons and enhanced 5-HT release. Buspirone also displays a weak affinity for serotonin 5HT2 receptors and acts as a weak antagonist on dopamine D2 autoreceptors, although there is not much evidence that the action at these receptors contribute to the anxiolytic effect of buspirone. It acts as an antagonist at presynaptic dopamine D3 and D4 receptors and may bind to alpha-1 adrenergic receptors as a partial agonist. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Buspirone is rapidly absorbed following oral administration. Bioavailability is low and variable (approximately 5%) due to extensive first pass metabolism. While absorption of buspirone is decreased with concomitant food intake, the first-pass metabolism of the drug is also decreased, resulting in an increased bioavailability as well as increased Cmax and AUC. Following oral administration of single oral doses of 20 mg, the Cmax ranged from 1 to 6 ng/mL and the Tmax ranged from 40 to 90 minutes. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the volume of distribution was 5.3 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Based on the findings of an in vitro protein binding study, approximately 86% of buspirone is bound to plasma proteins. It is mainly bound to serum albumin and alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Buspirone is extensively metabolized upon administration, where it primarily undergoes hepatic oxidation mediated by the CYP3A4 enzyme. Hydroxylated derivatives are produced, including a pharmacologically active metabolite 1-pyrimidinylpiperazine (1-PP). In animal studies, 1-PP possessed about one quarter of the pharmacological activity of buspirone. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): A single-dose pharmacokinetic studies using 14C-labeled buspirone demonstrated that about 29-63% of the dose administered was excreted in the urine within 24 hours, primarily in the form of metabolites. About 18% to 38% of the dose was eliminated via fecal excretion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): In a single-dose pharmacokinetic study of 14C-labeled buspirone, the average elimination half-life of unchanged buspirone following administration of single doses ranging from 10 to 40 mg was about 2 to 3 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In a pharmacokinetic study assessing buspirone over the dose range of 10 to 40 mg, the systemic clearance was 1.7 L/h/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 of buspirone is 196 mg/kg in rat, 655 mg/kg in mouse, 586 mg/kg in dog, and 356 mg/kg in monkey. The intraperitoneal LD 50 is 136 mg/kg in rat and 146 mg/kg in mouse. In clinical pharmacology trials, administration of buspirone at the dose of 375 mg/day resulted in symptoms of nausea, vomiting, dizziness, drowsiness, miosis, and gastric distress. Few cases of overdosage that have been reported usually resulted in complete recovery. In case of overdose, the use of general symptomatic and supportive treatment is recommended along with immediate gastric lavage and monitoring of respiration, pulse, and blood pressure. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Buspar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Buspiron Buspirona Buspirone Buspironum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Buspirone is an anxiolytic agent used for short-term treatment of generalized anxiety and second-line treatment of depression. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Busulfan interact?

•Drug A: Adalimumab •Drug B: Busulfan •Severity: MAJOR •Description: The metabolism of Busulfan can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 32% bound to plasma proteins and 47% bound to red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 2.6 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Busulfex, Myleran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,4-Dimesyloxybutane Busulfan Busulfano Busulfanum Busulphan •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Busulfan is an alkylating agent used to treat chronic myelogenous leukemia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Busulfan interact? Information: •Drug A: Adalimumab •Drug B: Busulfan •Severity: MAJOR •Description: The metabolism of Busulfan can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For use in combination with cyclophosphamide as a conditioning regimen prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous (myeloid, myelocytic, granulocytic) leukemia (FDA has designated busulfan as an orphan drug for this use). It is also used as a component of pretransplant conditioning regimens in patients undergoing bone marrow transplantation for acute myeloid leukemia and nonmalignant diseases. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Busulfan is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn leads to a miscoding of DNA. Alkylating agents are cell cycle-nonspecific and work by three different mechanisms, all of which achieve the same end result - disruption of DNA function and cell death. Overexpression of MGST2, a glutathione s-transferase, is thought to confer resistance to busulfan. The role of MGST2 in the metabolism of busulfan is unknown however. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Busulfan is an alkylating agent that contains 2 labile methanesulfonate groups attached to opposite ends of a 4-carbon alkyl chain. Once busulfan is hydrolyzed, the methanesulfonate groups are released and carbonium ions are produced. These carbonium ions alkylate DNA, which results in the interference of DNA replication and RNA transcription, ultimately leading to the disruption of nucleic acid function. Specifically, its mechanism of action through alkylation produces guanine-adenine intrastrand crosslinks. These crosslinks occur through a SN2 reaction guanine N7 nucleophilically attacks the carbon adjacent to the mesylate leaving group. This kind of damage cannot be repaired by cellular machinery and thus the cell undergoes apoptosis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Completely absorbed from the gastrointestinal tract. Busulfan is a small, highly lipophilic molecule that crosses the blood-brain-barrier. The absolute bioavailability, if a single 2 mg IV bolus injection is given to adult patients, is 80% ± 20%. In children (1.5 - 6 years old), the absolute bioavailability was 68% ± 31%. When a single oral dose is given to patients, the area under the curve (AUC) was 130 ng•hr/mL. The peak plasma concentration when given orally is 30 ng/mL (after dose normalization to 2 mg). It takes 0.9 hours to reach peak plasma concentration after dose normalization to 4 mg. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 32% bound to plasma proteins and 47% bound to red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Busulfan is extensively metabolizes in the hepatic. Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. GSTA1 is the primary GST isoform that facilitates the the metabolism of busulfan. Other GST isoforms that are also involved are GSTM1 and GSTP1. At least 12 metabolites have been identified among which tetrahydrothiophene, tetrahydrothiophene 12-oxide, sulfolane, and 3-hydroxysulfolane were identified. These metabolites do not have cytotoxic activity. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following administration of 14C- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. Less than 2% of the administered dose is excreted in the urine unchanged within 24 hours. Elimination of busulfan is independent of renal function. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 2.6 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 2.52 ml/min/kg [Following an infusion of dose of 0.8 mg/kg every six hours, for a total of 16 doses over four days] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Signs of overdose include allergic reaction, unusual bleeding or bruising, sudden weakness or unusual fatigue, persistent cough, congestion, or shortness of breath; flank, stomach or joint pain; pronounced nausea, vomiting, diarrhea, dizziness, confusion, or darkening of the skin, chills, fever, collapse, and loss of consciousness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Busulfex, Myleran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1,4-Dimesyloxybutane Busulfan Busulfano Busulfanum Busulphan •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Busulfan is an alkylating agent used to treat chronic myelogenous leukemia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Cabazitaxel interact?

•Drug A: Adalimumab •Drug B: Cabazitaxel •Severity: MAJOR •Description: The metabolism of Cabazitaxel can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel -containing treatment regimen. In Europe and Canada, it can also be used in combination with prednisolone. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cabazitaxel demonstrates a broad spectrum of antitumour activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas. Cabazitaxel has a low affinity to P-glycoprotein, allowing it to penetrate the blood-brain barrier without being subject to extensive P-gp-mediated active efflux. Cabazitaxel works against docetaxel-sensitive tumours and tumour models resistant to docetaxel and other chemotherapy drugs. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Microtubules are cytoskeletal polymers that regulate cell shape, vesicle transport, cell signalling, and cell division. They are made up of alpha-tubulin and beta-tubulin heterodimers. Microtubules extend toward the mitotic spindle during mitosis to allow the separation and distribution of chromosomes during cell division. Cabazitaxel binds to the N-terminal amino acids of the beta-tubulin subunit and promotes microtubule polymerization while simultaneously inhibiting disassembly: this results in the stabilization of microtubules, preventing microtubule cell division. Cabazitaxel ultimately blocks mitotic and interphase cellular functions and tumour proliferation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m every three weeks, the mean C max in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (T max ). The mean AUC in patients with metastatic prostate cancer was 991 ng x h/mL (CV 34%). No major deviation from the dose proportionality was observed from 10 to 30 mg/m in patients with advanced solid tumours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Steady-state volume of distribution (V ss ) was 4,864 L (2,643 L/m for a patient with a median BSA of 1.84 m ). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 ng/mL. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): More than 95% of cabazitaxel is extensively metabolized in the liver. CYP3A4 and CYP3A5 are responsible for 80% to 90% of drug metabolism, while CYP2C8 is involved to a lesser extent. While cabazitaxel is the main circulating moiety in human plasma, seven metabolites have been detected in plasma, including three active metabolites arising from O-demethylation - docetaxel, RPR112698, and RPR123142. The main metabolite accounts for 5% of total cabazitaxel exposure. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After a one-hour intravenous infusion [ C]-cabazitaxel 25 mg/m, approximately 80% of the administered dose was eliminated within two weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose), while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). Around 20 metabolites of cabazitaxel are excreted into human urine and feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of four minutes, two hours, and 95 hours, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m for a patient with a median BSA of 1.84 m ) in patients with metastatic prostate cancer. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 in rats is 500 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Jevtana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cabazitaxel is an antineoplastic agent used in combination with corticosteroids to treat metastatic castration-resistant prostate cancer in patients previously treated with a docetaxel-containing treatment regimen.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Cabazitaxel interact? Information: •Drug A: Adalimumab •Drug B: Cabazitaxel •Severity: MAJOR •Description: The metabolism of Cabazitaxel can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cabazitaxel is indicated, in combination with prednisone, for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel -containing treatment regimen. In Europe and Canada, it can also be used in combination with prednisolone. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cabazitaxel demonstrates a broad spectrum of antitumour activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas. Cabazitaxel has a low affinity to P-glycoprotein, allowing it to penetrate the blood-brain barrier without being subject to extensive P-gp-mediated active efflux. Cabazitaxel works against docetaxel-sensitive tumours and tumour models resistant to docetaxel and other chemotherapy drugs. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Microtubules are cytoskeletal polymers that regulate cell shape, vesicle transport, cell signalling, and cell division. They are made up of alpha-tubulin and beta-tubulin heterodimers. Microtubules extend toward the mitotic spindle during mitosis to allow the separation and distribution of chromosomes during cell division. Cabazitaxel binds to the N-terminal amino acids of the beta-tubulin subunit and promotes microtubule polymerization while simultaneously inhibiting disassembly: this results in the stabilization of microtubules, preventing microtubule cell division. Cabazitaxel ultimately blocks mitotic and interphase cellular functions and tumour proliferation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Based on the population pharmacokinetic analysis, after an intravenous dose of cabazitaxel 25 mg/m every three weeks, the mean C max in patients with metastatic prostate cancer was 226 ng/mL (CV 107%) and was reached at the end of the one-hour infusion (T max ). The mean AUC in patients with metastatic prostate cancer was 991 ng x h/mL (CV 34%). No major deviation from the dose proportionality was observed from 10 to 30 mg/m in patients with advanced solid tumours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Steady-state volume of distribution (V ss ) was 4,864 L (2,643 L/m for a patient with a median BSA of 1.84 m ). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 ng/mL. Cabazitaxel is mainly bound to human serum albumin (82%) and lipoproteins (88% for HDL, 70% for LDL, and 56% for VLDL). The in vitro blood-to-plasma concentration ratio in human blood ranged from 0.90 to 0.99, indicating that cabazitaxel was equally distributed between blood and plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): More than 95% of cabazitaxel is extensively metabolized in the liver. CYP3A4 and CYP3A5 are responsible for 80% to 90% of drug metabolism, while CYP2C8 is involved to a lesser extent. While cabazitaxel is the main circulating moiety in human plasma, seven metabolites have been detected in plasma, including three active metabolites arising from O-demethylation - docetaxel, RPR112698, and RPR123142. The main metabolite accounts for 5% of total cabazitaxel exposure. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After a one-hour intravenous infusion [ C]-cabazitaxel 25 mg/m, approximately 80% of the administered dose was eliminated within two weeks. Cabazitaxel is mainly excreted in the feces as numerous metabolites (76% of the dose), while renal excretion of cabazitaxel and metabolites account for 3.7% of the dose (2.3% as unchanged drug in urine). Around 20 metabolites of cabazitaxel are excreted into human urine and feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following a one-hour intravenous infusion, plasma concentrations of cabazitaxel can be described by a three-compartment pharmacokinetic model with α-, β-, and γ- half-lives of four minutes, two hours, and 95 hours, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Based on the population pharmacokinetic analysis, cabazitaxel has a plasma clearance of 48.5 L/h (CV 39%; 26.4 L/h/m for a patient with a median BSA of 1.84 m ) in patients with metastatic prostate cancer. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 in rats is 500 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Jevtana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cabazitaxel is an antineoplastic agent used in combination with corticosteroids to treat metastatic castration-resistant prostate cancer in patients previously treated with a docetaxel-containing treatment regimen. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Cabergoline interact?

•Drug A: Adalimumab •Drug B: Cabergoline •Severity: MAJOR •Description: The metabolism of Cabergoline can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of hyperprolactinemic disorders, either idiopathic or due to prolactinoma (prolactin-secreting adenomas). May also be used to manage symptoms of Parkinsonian Syndrome as monotherapy during initial symptomatic management or as an adjunct to levodopa therapy during advanced stages of disease. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cabergoline stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 - and D 3 -receptors. It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT) 2B, 5-HT 2A, 5-HT 1D, dopamine D 4, 5-HT 1A, dopamine D 1, 5-HT 1B and 5-HT 2C receptors and antagonist activity on α 2B, α 2A, and α 2C receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α 1,- and α 2 - adrenergic, and 5-HT 1 - and 5-HT 2 -serotonin receptors. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): First-pass effect is seen, however the absolute bioavailability is unknown. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. The main metabolite identified in urine is 6-allyl-8b-carboxy-ergoline (4-6% of dose). Three other metabolites were identified urine (less than 3% of dose). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life is estimated from urinary data of 12 healthy subjects to range between 63 to 69 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): renal cl=0,008 L/min nonrenal cl=3.2 L/min •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dostinex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cabergolina Cabergoline Cabergolinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Cabergoline interact? Information: •Drug A: Adalimumab •Drug B: Cabergoline •Severity: MAJOR •Description: The metabolism of Cabergoline can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of hyperprolactinemic disorders, either idiopathic or due to prolactinoma (prolactin-secreting adenomas). May also be used to manage symptoms of Parkinsonian Syndrome as monotherapy during initial symptomatic management or as an adjunct to levodopa therapy during advanced stages of disease. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cabergoline stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D 1 and D 5 subreceptors, which are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D 2, D 3 and D 4 subreceptors, which are associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D 2 and D 3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D 2 - and D 3 -receptors. It also exhibits: agonist activity (in order of decreasing binding affinities) on 5-hydroxytryptamine (5-HT) 2B, 5-HT 2A, 5-HT 1D, dopamine D 4, 5-HT 1A, dopamine D 1, 5-HT 1B and 5-HT 2C receptors and antagonist activity on α 2B, α 2A, and α 2C receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT 2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The dopamine D 2 receptor is a 7-transmembrane G-protein coupled receptor associated with G i proteins. In lactotrophs, stimulation of dopamine D 2 causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D 2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders. Cabergoline is a long-acting dopamine receptor agonist with a high affinity for D2 receptors. Receptor-binding studies indicate that cabergoline has low affinity for dopamine D1, α 1,- and α 2 - adrenergic, and 5-HT 1 - and 5-HT 2 -serotonin receptors. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): First-pass effect is seen, however the absolute bioavailability is unknown. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Moderately bound (40% to 42%) to human plasma proteins in a concentration-independent manner. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cabergoline is extensively metabolized, predominately via hydrolysis of the acylurea bond of the urea moiety. Cytochrome P-450 mediated metabolism appears to be minimal. The main metabolite identified in urine is 6-allyl-8b-carboxy-ergoline (4-6% of dose). Three other metabolites were identified urine (less than 3% of dose). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After oral dosing of radioactive cabergoline to five healthy volunteers, approximately 22% and 60% of the dose was excreted within 20 days in the urine and feces, respectively. Less than 4% of the dose was excreted unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life is estimated from urinary data of 12 healthy subjects to range between 63 to 69 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): renal cl=0,008 L/min nonrenal cl=3.2 L/min •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dostinex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cabergolina Cabergoline Cabergolinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cabergoline is a dopamine receptor agonist used for the treatment of hyperprolactinemic conditions due to various causes. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Cabozantinib interact?

•Drug A: Adalimumab •Drug B: Cabozantinib •Severity: MAJOR •Description: The metabolism of Cabozantinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer. It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, peak plasma concentration was achieved in 2-5 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution is 349L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cabozantinib has extensive plasma protein binding (≥ 99.7%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%). •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Cabozantinib has a long half-life of 55 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): At steady state, the clearance is 4.4 L/hr. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cabometyx, Cometriq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cabozantinib is a tyrosine kinase inhibitor used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Cabozantinib interact? Information: •Drug A: Adalimumab •Drug B: Cabozantinib •Severity: MAJOR •Description: The metabolism of Cabozantinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cabozantinib is indicated for the treatment of progressive, metastatic medullary thyroid cancer. It is also indicated for the treatment of advanced renal cell carcinoma and for hepatocellular carcinoma in patients previously treated with sorafenib. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cabozantinib suppresses metastasis, angiogenesis, and oncognesis by inhibiting receptor tyrosine kinases. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cabozantinib inhibits specific receptor tyrosine kinases such as VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET, and TIE-2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, peak plasma concentration was achieved in 2-5 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution is 349L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cabozantinib has extensive plasma protein binding (≥ 99.7%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cabozantinib is metabolized mostly by CYP3A4 and, to a minor extent, by CYP2C9. Both enzyme produce an N-oxide metabolite. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cabozantinib is eliminated mostly by the feces (54%) and also by the urine (27%). •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Cabozantinib has a long half-life of 55 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): At steady state, the clearance is 4.4 L/hr. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Cabozantinib carries a warning of serious gastrointestinal fistulas and perforations, and potentially fatal hemoptysis and gastrointestinal hemorrhage. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cabometyx, Cometriq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cabozantinib is a tyrosine kinase inhibitor used to treat advanced renal cell carcinoma, hepatocellular carcinoma, and medullary thyroid cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Caffeine interact?

•Drug A: Adalimumab •Drug B: Caffeine •Severity: MODERATE •Description: The serum concentration of Caffeine can be decreased when it is combined with Adalimumab. •Extended Description: According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Caffeine is indicated for the short term treatment of apnea of prematurity in infants and off label for the prevention and treatment of bronchopulmonary dysplasia caused by premature birth. In addition, it is indicated in combination with sodium benzoate to treat respiratory depression resulting from an overdose with CNS depressant drugs. Caffeine has a broad range of over the counter uses, and is found in energy supplements, athletic enhancement products, pain relief products, as well as cosmetic products. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: General and cellular actions Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. Respiratory The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. Central nervous system Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. Renal system Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. Cardiovascular system Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of caffeine has not been determined for neonates or infants. In vitro studies indicate a protein binding of about 10%-36%. Caffeine is reversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2) also participate in the metabolism of caffeine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): In an average-sized adult or child above the age of 9, the half-life of caffeine is approximately 5 hours. Various characteristics and conditions can alter caffeine half-life. It can be reduced by up to 50% in smokers. Pregnant women show an increased half-life of 15 hours or higher, especially in the third trimester. The half-life in newborns is prolonged to about 8 hours at full-term and 100 hours in premature infants, likely due to reduced ability to metabolize it. Liver disease or drugs that inhibit CYP1A2 can increase caffeine half-life. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of caffeine varies, but on average, is about 0.078 L/kg/h (1.3 mL/min/kg). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD50 of caffeine in rats is 192 mg/kg. An acute fatal overdose of caffeine in humans is about 10–14 grams (equivalent to 150–200 mg/kg of body weight). Caffeine overdose In the case of caffeine overdose, seizures may occur, as caffeine is a central nervous system stimulant. It should be used with extreme caution in those with epilepsy or other seizure disorders. Symptoms of overdose may include nausea, vomiting, diarrhea, and gastrointestinal upset. Intoxication with caffeine is included in the World Health Organization’s International Classification of Diseases (ICD-10). Agitation, anxiety, restlessness, insomnia, tachycardia, tremors, tachycardia, psychomotor agitation, and, in some cases, death can occur, depending on the amount of caffeine consumed. Overdose is more likely to occur in individuals who do not consume caffeine regularly but consume energy drinks. Overdose management For a mild caffeine overdose, offer symptomatic treatment. In the case of a severe overdose, intubation for airway protection from changes in mental status or vomiting may be needed. Activated charcoal and hemodialysis can prevent further complications of an overdose and prevent absorption and metabolism. Benzodiazepine drugs can be administered to prevent or treat seizures. IV fluids and vasopressors may be necessary to combat hypotension associated with caffeine overdose. In addition, magnesium and beta blocking drugs can be used to treat arrhythmias that may occur, with defibrillation and resuscitation if the arrhythmias are lethal. Follow local ACLS protocols. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Anacin, Arthriten Inflammatory Pain, Ascomp, Bc Arthritis, Bc Original Formula, Diurex, Dvorah, Esgic, Exaprin, Excedrin, Excedrin Tension Headache, Fioricet, Fioricet With Codeine, Fiorinal, Goody's Extra Strength, Goody's Headache Relief Shot, Goody's PM, Midol Complete, Midol Cramps & Bodyaches, Migergot, Norgesic, Norgesic Forte, Orbivan, Orphengesic, Pamprin Max Formula, Peyona, Stanback Headache Powder Reformulated Jan 2011, Trezix, Trianal, Trianal C, Triatec, Triatec-8, Vanatol, Vanatol S, Vanquish, Vivarin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-methyltheobromine 7-methyltheophylline Cafeína Caféine Caffeine Caffeinum Coffein Coffeinum Guaranine Koffein Mateína Methyltheobromine Teína Thein Theine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Caffeine is a stimulant present in tea, coffee, cola beverages, analgesic drugs, and agents used to increase alertness. It is also used in to prevent and treat pulmonary complications of premature birth.

According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. The severity of the interaction is moderate.

Question: Does Adalimumab and Caffeine interact? Information: •Drug A: Adalimumab •Drug B: Caffeine •Severity: MODERATE •Description: The serum concentration of Caffeine can be decreased when it is combined with Adalimumab. •Extended Description: According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Caffeine is indicated for the short term treatment of apnea of prematurity in infants and off label for the prevention and treatment of bronchopulmonary dysplasia caused by premature birth. In addition, it is indicated in combination with sodium benzoate to treat respiratory depression resulting from an overdose with CNS depressant drugs. Caffeine has a broad range of over the counter uses, and is found in energy supplements, athletic enhancement products, pain relief products, as well as cosmetic products. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Caffeine stimulates the central nervous system (CNS), heightening alertness, and sometimes causing restlessness and agitation. It relaxes smooth muscle, stimulates the contraction of cardiac muscle, and enhances athletic performance. Caffeine promotes gastric acid secretion and increases gastrointestinal motility. It is often combined in products with analgesics and ergot alkaloids, relieving the symptoms of migraine and other types of headaches. Finally, caffeine acts as a mild diuretic. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of caffeine is complex, as it impacts several body systems, which are listed below. The effects as they relate to various body systems are described as follows: General and cellular actions Caffeine exerts several actions on cells, but the clinical relevance is poorly understood. One probable mechanism is the inhibition of nucleotide phosphodiesterase enzymes, adenosine receptors, regulation of calcium handling in cells, and participates in adenosine receptor antagonism. Phosphodiesterase enzymes regulate cell function via actions on second messengers cAMP and cGMP. This causes lipolysis through activation of hormone-sensitive lipases, releasing fatty acids and glycerol. Respiratory The exact mechanism of action of caffeine in treating apnea related to prematurity is unknown, however, there are several proposed mechanisms, including respiratory center stimulation in the central nervous system, a reduced threshold to hypercapnia with increased response, and increased consumption of oxygen, among others. The blocking of the adenosine receptors enhances respiratory drive via an increase in brain medullary response to carbon dioxide, stimulating ventilation and respiratory drive, while increasing contractility of the diaphragm. Central nervous system Caffeine demonstrates antagonism of all 4 adenosine receptor subtypes (A1, A2a, A2b, A3) in the central nervous system. Caffeine's effects on alertness and combatting drowsiness are specifically related to the antagonism of the A2a receptor. Renal system Caffeine has diuretic effects due to is stimulatory effects on renal blood flow, increase in glomerular filtration, and increase in sodium excretion. Cardiovascular system Adenosine receptor antagonism at the A1 receptor by caffeine stimulates inotropic effects in the heart. Blocking of adenosine receptors promotes catecholamine release, leading to stimulatory effects occurring in the heart and the rest of the body. In the blood vessels, caffeine exerts direct antagonism of adenosine receptors, causing vasodilation. It stimulates the endothelial cells in the blood vessel wall to release nitric oxide, potentiating blood vessel relaxation. Catecholamine release, however, antagonizes this and exerts inotropic and chronotropic effects on the heart, ultimately leading to vasoconstriction. Finally, caffeine is shown to raise systolic blood pressure measurements by 5 to 10 mmHg when it is not taken regularly, versus no effect in those who consume it regularly. The vasoconstricting effects of caffeine are beneficial in migraines and other types of headache, which are normally caused by vasodilation in the brain. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of caffeine has not been determined for neonates or infants. In vitro studies indicate a protein binding of about 10%-36%. Caffeine is reversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2) also participate in the metabolism of caffeine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): In an average-sized adult or child above the age of 9, the half-life of caffeine is approximately 5 hours. Various characteristics and conditions can alter caffeine half-life. It can be reduced by up to 50% in smokers. Pregnant women show an increased half-life of 15 hours or higher, especially in the third trimester. The half-life in newborns is prolonged to about 8 hours at full-term and 100 hours in premature infants, likely due to reduced ability to metabolize it. Liver disease or drugs that inhibit CYP1A2 can increase caffeine half-life. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of caffeine varies, but on average, is about 0.078 L/kg/h (1.3 mL/min/kg). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD50 of caffeine in rats is 192 mg/kg. An acute fatal overdose of caffeine in humans is about 10–14 grams (equivalent to 150–200 mg/kg of body weight). Caffeine overdose In the case of caffeine overdose, seizures may occur, as caffeine is a central nervous system stimulant. It should be used with extreme caution in those with epilepsy or other seizure disorders. Symptoms of overdose may include nausea, vomiting, diarrhea, and gastrointestinal upset. Intoxication with caffeine is included in the World Health Organization’s International Classification of Diseases (ICD-10). Agitation, anxiety, restlessness, insomnia, tachycardia, tremors, tachycardia, psychomotor agitation, and, in some cases, death can occur, depending on the amount of caffeine consumed. Overdose is more likely to occur in individuals who do not consume caffeine regularly but consume energy drinks. Overdose management For a mild caffeine overdose, offer symptomatic treatment. In the case of a severe overdose, intubation for airway protection from changes in mental status or vomiting may be needed. Activated charcoal and hemodialysis can prevent further complications of an overdose and prevent absorption and metabolism. Benzodiazepine drugs can be administered to prevent or treat seizures. IV fluids and vasopressors may be necessary to combat hypotension associated with caffeine overdose. In addition, magnesium and beta blocking drugs can be used to treat arrhythmias that may occur, with defibrillation and resuscitation if the arrhythmias are lethal. Follow local ACLS protocols. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Anacin, Arthriten Inflammatory Pain, Ascomp, Bc Arthritis, Bc Original Formula, Diurex, Dvorah, Esgic, Exaprin, Excedrin, Excedrin Tension Headache, Fioricet, Fioricet With Codeine, Fiorinal, Goody's Extra Strength, Goody's Headache Relief Shot, Goody's PM, Midol Complete, Midol Cramps & Bodyaches, Migergot, Norgesic, Norgesic Forte, Orbivan, Orphengesic, Pamprin Max Formula, Peyona, Stanback Headache Powder Reformulated Jan 2011, Trezix, Trianal, Trianal C, Triatec, Triatec-8, Vanatol, Vanatol S, Vanquish, Vivarin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 1-methyltheobromine 7-methyltheophylline Cafeína Caféine Caffeine Caffeinum Coffein Coffeinum Guaranine Koffein Mateína Methyltheobromine Teína Thein Theine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Caffeine is a stimulant present in tea, coffee, cola beverages, analgesic drugs, and agents used to increase alertness. It is also used in to prevent and treat pulmonary complications of premature birth. Output: According to the FDA label for adalimumab 5 the formation of CYP450 enzymes may be suppressed by increased levels of cytokines (for example, TNFα, IL-6) during chronic inflammation. It is possible for a drug that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes, increasing the metabolism of xanthine derivatives. These drugs are primarily metabolized by CYP450 enzymes. The severity of the interaction is moderate.

Does Adalimumab and Canakinumab interact?

•Drug A: Adalimumab •Drug B: Canakinumab •Severity: MAJOR •Description: The risk or severity of infection and neutropenia can be increased when Adalimumab is combined with Canakinumab. •Extended Description: In clinical trials, canakinumab has not been administered concomitantly with TNF inhibitors.5 Nevertheless, as canakinumab predominantly elicits its pharmacological actions as an interleukin-1β blocker, studies have shown that one of the important adverse effects associated with the medication is its capacity for causing immunosuppression and infections like neutropenia. At the same time, TNF-α inhibitors are also inherently associated with immunosuppresive properties. Subsequently, the concomitant use of canakinumab and TNF-α inhibitors raises a concern regarding possible increases in the risk of serious infection for patients. In particular, in a study involving the concurrent use of the related interleukin -1 receptor antagonist anakinra and TNF-α inhibitor etanercept therapy in rheumatoid arthritis patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). Moreover, the combination of anakinra and the TNF-α inhibitor etanercept did not provide any added benefit compared to using either agent alone. It is consequently believed that the use of canakinumab with TNF inhibitors may also result in similar immunosuppressive toxicities. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Canakinumab is indicated for the treatment of periodic fever syndromes in specific patient populations. In patients ≥4 years of age, canakinumab is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). In adult and pediatric patients, canakinumab is also indicated for the treatment of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF). Canakinumab is additionally indicated in patients ≥2 years of age for the treatment of active Still's disease, including Adult-Onset Still's Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA). Canakinumab is also indicated for the treatment of gout flares in adult patients in whom standard therapies (e.g. NSAIDs, colchicine) are contraindicated, not tolerated, or ineffective, and in whom repeated courses of corticosteroids are not appropriate. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Canakinumab neutralizes the activity of human IL-1β, which is involved in several inflammatory disorders. Canakinumab has promising clinical safety and pharmacokinetic properties, and demonstrated potential for the treatment of cryopyrin-associated periodic syndromes (CAPS), systemic juvenile idiopathic arthritis (SJIA), and possibly for other complex inflammatory diseases, such as rheumatoid arthritis, COPD disease and ocular diseases. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): In inflammatory diseases involving Cryopyrin-Associated Periodic Syndromes (CAPS), interleukin-1 beta (IL-1β) is excessively activated and drives inflammation. The protein cryopyrin controls the activation of IL-1β, and mutations in cryopyrin's gene, NLRP-3, up-regulate IL-1β activation. Canakinumab binds to human IL-1β and neutralizes its inflammatory activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absolute bioavailability of subcutaneously administered canakinumab is estimated to be 66%. Peak serum concentration is 16 ± 3.5 mcg/mL and occurs approximately 7 days following a single subcutaneous dose of 150mg. Exposure to canakinumab increases proportionately to the administered dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The steady-state volume of distribution of canakinumab is variable based on weight - it was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, 3.2 liters in a SJIA patient weighing 33 kg, 6.34 liters for a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 7.9 liters in a typical patient with gout flares weighing 93 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Canakinumab binds to plasma IL-1β, but plasma protein binding has not been quantified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Canakinumab, like other therapeutic proteins, is likely degraded via non-specific catabolic processes to smaller peptides and amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The route of elimination for canakinumab has not yet been determined. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 26 days •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of canakinumab is variable based on weight - it was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg, 0.11 L/day in an SJIA patient weighing 33 kg, 0.17 L/day in a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 0.23 L/day in a typical patient with gout flares of body weight 93 kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There are no confirmed cases of overdosage with canakinumab. In the event of an overdose, the patient should be monitored closely and appropriate symptomatic treatment should be administered immediately as clinically indicated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ilaris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Canakinumab is an interleukin-1β blocker used to treat Periodic Fever Syndromes such as Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF), and also to treat active Systemic Juvenile Idiopathic Arthritis (SJIA).

In clinical trials, canakinumab has not been administered concomitantly with TNF inhibitors.5 Nevertheless, as canakinumab predominantly elicits its pharmacological actions as an interleukin-1β blocker, studies have shown that one of the important adverse effects associated with the medication is its capacity for causing immunosuppression and infections like neutropenia. At the same time, TNF-α inhibitors are also inherently associated with immunosuppresive properties. Subsequently, the concomitant use of canakinumab and TNF-α inhibitors raises a concern regarding possible increases in the risk of serious infection for patients. In particular, in a study involving the concurrent use of the related interleukin -1 receptor antagonist anakinra and TNF-α inhibitor etanercept therapy in rheumatoid arthritis patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). Moreover, the combination of anakinra and the TNF-α inhibitor etanercept did not provide any added benefit compared to using either agent alone. It is consequently believed that the use of canakinumab with TNF inhibitors may also result in similar immunosuppressive toxicities. The severity of the interaction is major.

Question: Does Adalimumab and Canakinumab interact? Information: •Drug A: Adalimumab •Drug B: Canakinumab •Severity: MAJOR •Description: The risk or severity of infection and neutropenia can be increased when Adalimumab is combined with Canakinumab. •Extended Description: In clinical trials, canakinumab has not been administered concomitantly with TNF inhibitors.5 Nevertheless, as canakinumab predominantly elicits its pharmacological actions as an interleukin-1β blocker, studies have shown that one of the important adverse effects associated with the medication is its capacity for causing immunosuppression and infections like neutropenia. At the same time, TNF-α inhibitors are also inherently associated with immunosuppresive properties. Subsequently, the concomitant use of canakinumab and TNF-α inhibitors raises a concern regarding possible increases in the risk of serious infection for patients. In particular, in a study involving the concurrent use of the related interleukin -1 receptor antagonist anakinra and TNF-α inhibitor etanercept therapy in rheumatoid arthritis patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). Moreover, the combination of anakinra and the TNF-α inhibitor etanercept did not provide any added benefit compared to using either agent alone. It is consequently believed that the use of canakinumab with TNF inhibitors may also result in similar immunosuppressive toxicities. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Canakinumab is indicated for the treatment of periodic fever syndromes in specific patient populations. In patients ≥4 years of age, canakinumab is indicated for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial Cold Auto-inflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS). In adult and pediatric patients, canakinumab is also indicated for the treatment of Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Hyperimmunoglobulin D Syndrome (HIDS)/Mevalonate Kinase Deficiency (MKD), and Familial Mediterranean Fever (FMF). Canakinumab is additionally indicated in patients ≥2 years of age for the treatment of active Still's disease, including Adult-Onset Still's Disease (AOSD) and Systemic Juvenile Idiopathic Arthritis (SJIA). Canakinumab is also indicated for the treatment of gout flares in adult patients in whom standard therapies (e.g. NSAIDs, colchicine) are contraindicated, not tolerated, or ineffective, and in whom repeated courses of corticosteroids are not appropriate. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Canakinumab neutralizes the activity of human IL-1β, which is involved in several inflammatory disorders. Canakinumab has promising clinical safety and pharmacokinetic properties, and demonstrated potential for the treatment of cryopyrin-associated periodic syndromes (CAPS), systemic juvenile idiopathic arthritis (SJIA), and possibly for other complex inflammatory diseases, such as rheumatoid arthritis, COPD disease and ocular diseases. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): In inflammatory diseases involving Cryopyrin-Associated Periodic Syndromes (CAPS), interleukin-1 beta (IL-1β) is excessively activated and drives inflammation. The protein cryopyrin controls the activation of IL-1β, and mutations in cryopyrin's gene, NLRP-3, up-regulate IL-1β activation. Canakinumab binds to human IL-1β and neutralizes its inflammatory activity by blocking its interaction with IL-1 receptors, but it does not bind IL-1α or IL-1 receptor antagonist (IL-1ra). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absolute bioavailability of subcutaneously administered canakinumab is estimated to be 66%. Peak serum concentration is 16 ± 3.5 mcg/mL and occurs approximately 7 days following a single subcutaneous dose of 150mg. Exposure to canakinumab increases proportionately to the administered dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The steady-state volume of distribution of canakinumab is variable based on weight - it was estimated to be 6.01 liters in a typical CAPS patient weighing 70 kg, 3.2 liters in a SJIA patient weighing 33 kg, 6.34 liters for a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 7.9 liters in a typical patient with gout flares weighing 93 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Canakinumab binds to plasma IL-1β, but plasma protein binding has not been quantified. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Canakinumab, like other therapeutic proteins, is likely degraded via non-specific catabolic processes to smaller peptides and amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The route of elimination for canakinumab has not yet been determined. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 26 days •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of canakinumab is variable based on weight - it was estimated to be 0.174 L/day in a typical CAPS patient weighing 70 kg, 0.11 L/day in an SJIA patient weighing 33 kg, 0.17 L/day in a Periodic Fever Syndrome (TRAPS, HIDS/MKD, FMF) patient weighing 70 kg and 0.23 L/day in a typical patient with gout flares of body weight 93 kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There are no confirmed cases of overdosage with canakinumab. In the event of an overdose, the patient should be monitored closely and appropriate symptomatic treatment should be administered immediately as clinically indicated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ilaris •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Canakinumab is an interleukin-1β blocker used to treat Periodic Fever Syndromes such as Cryopyrin-Associated Periodic Syndromes (CAPS) and Familial Mediterranean Fever (FMF), and also to treat active Systemic Juvenile Idiopathic Arthritis (SJIA). Output: In clinical trials, canakinumab has not been administered concomitantly with TNF inhibitors.5 Nevertheless, as canakinumab predominantly elicits its pharmacological actions as an interleukin-1β blocker, studies have shown that one of the important adverse effects associated with the medication is its capacity for causing immunosuppression and infections like neutropenia. At the same time, TNF-α inhibitors are also inherently associated with immunosuppresive properties. Subsequently, the concomitant use of canakinumab and TNF-α inhibitors raises a concern regarding possible increases in the risk of serious infection for patients. In particular, in a study involving the concurrent use of the related interleukin -1 receptor antagonist anakinra and TNF-α inhibitor etanercept therapy in rheumatoid arthritis patients, the rate of serious infections in the combination arm (7%) was higher than with etanercept alone (0%). Moreover, the combination of anakinra and the TNF-α inhibitor etanercept did not provide any added benefit compared to using either agent alone. It is consequently believed that the use of canakinumab with TNF inhibitors may also result in similar immunosuppressive toxicities. The severity of the interaction is major.

Does Adalimumab and Candesartan cilexetil interact?

•Drug A: Adalimumab •Drug B: Candesartan cilexetil •Severity: MODERATE •Description: The metabolism of Candesartan cilexetil can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.13 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via bile). •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Approximately 9 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.37 mL/min/kg •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Atacand, Atacand Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Candesartan cilexetil is an angiotensin receptor blocker used to treat hypertension, systolic hypertension, left ventricular hypertrophy, and delay progression of diabetic nephropathy.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Candesartan cilexetil interact? Information: •Drug A: Adalimumab •Drug B: Candesartan cilexetil •Severity: MODERATE •Description: The metabolism of Candesartan cilexetil can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): May be used as a first line agent to treat uncomplicated hypertension, isolated systolic hypertension and left ventricular hypertrophy. May be used as a first line agent to delay progression of diabetic nephropathy. Candesartan may be also used as a second line agent in the treatment of congestive heart failure, systolic dysfunction, myocardial infarction and coronary artery disease in those intolerant of ACE inhibitors. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Candesartan cilexetil is an ARB prodrug that is rapidly converted to candesartan, its active metabolite, during absorption from the gastrointestinal tract. Candesartan confers blood pressure lowering effects by antagonizing the hypertensive effects of angiotensin II via the RAAS. RAAS is a homeostatic mechanism for regulating hemodynamics, water and electrolyte balance. During sympathetic stimulation or when renal blood pressure or blood flow is reduced, renin is released from granular cells of the juxtaglomerular apparatus in the kidneys. Renin cleaves circulating angiotensinogen to angiotensin I, which is cleaved by angiotensin converting enzyme (ACE) to angiotensin II. Angiotensin II increases blood pressure by increasing total peripheral resistance, increasing sodium and water reabsorption in the kidneys via aldosterone secretion, and altering cardiovascular structure. Angiotensin II binds to two receptors: type-1 angiotensin II receptor (AT1) and type-2 angiotensin II receptor (AT2). AT1 is a G-protein coupled receptor (GPCR) that mediates the vasoconstrictive and aldosterone-secreting effects of angiotensin II. Studies performed in recent years suggest that AT2 antagonizes AT1-mediated effects and directly affects long-term blood pressure control by inducing vasorelaxation and increasing urinary sodium excretion. Angiotensin receptor blockers (ARBs) are non-peptide competitive inhibitors of AT1. ARBs block the ability of angiotensin II to stimulate pressor and cell proliferative effects. Unlike ACE inhibitors, ARBs do not affect bradykinin-induced vasodilation. The overall effect of ARBs is a decrease in blood pressure. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Candesartan selectively blocks the binding of angiotensin II to AT1 in many tissues including vascular smooth muscle and the adrenal glands. This inhibits the AT1-mediated vasoconstrictive and aldosterone-secreting effects of angiotensin II and results in an overall decrease in blood pressure. Candesartan is greater than 10,000 times more selective for AT1 than AT2. Inhibition of aldosterone secretion may increase sodium and water excretion while decreasing potassium excretion. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following administration of the candesartan cilexetil prodrug, the absolute bioavailability of candesartan was estimated to be 15%. Food with a high fat content has no effect on the bioavailability of candesartan from candesartan cilexetil. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.13 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Candesartan is highly bound to plasma proteins (>99%) and does not penetrate red blood cells. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The prodrug candesartan cilexetil undergoes rapid and complete ester hydrolysis in the intestinal wall to form the active drug, candesartan. Elimination of candesartan is primarily as unchanged drug in the urine and, by the biliary route, in the feces. Minor hepatic metabolism of candesartan (<20%) occurs by O-deethylation via cytochrome P450 2C9 to form an inactive metabolite. Candesartan undergoes N-glucuronidation in the tetrazole ring by uridine diphosphate glucuronosyltransferase 1A3 (UGT1A3). O-glucuronidation may also occur. 75% of candesartan is excreted as unchanged drug in urine and feces. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): When candesartan is administered orally, about 26% of the dose is excreted unchanged in urine. Candesartan is mainly excreted unchanged in urine and feces (via bile). •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Approximately 9 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 0.37 mL/min/kg •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No lethality was observed in acute toxicity studies in mice, rats and dogs given single oral doses of up to 2000 mg/kg of candesartan cilexetil or in rats given single oral doses of up to 2000 mg/kg of candesartan cilexetil in combination with 1000 mg/kg of hydrochlorothiazide. In mice given single oral doses of the primary metabolite, candesartan, the minimum lethal dose was greater than 1000 mg/kg but less than 2000 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Atacand, Atacand Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Candesartan cilexetil is an angiotensin receptor blocker used to treat hypertension, systolic hypertension, left ventricular hypertrophy, and delay progression of diabetic nephropathy. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cannabidiol interact?

•Drug A: Adalimumab •Drug B: Cannabidiol •Severity: MODERATE •Description: The metabolism of Cannabidiol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): When used in combination with delta-9-tetrahydrocannabinol as the product Sativex, cannabidiol was given a standard marketing authorization (ie. a Notice of Compliance (NOC)) by Health Canada for the following indications: 1) as adjunctive treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis (MS) who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy; Due to the need for confirmatory studies to verify the clinical benefit coupled with the promising nature of the clinical evidence, Sativex was also given a Notice of Compliance with Conditions (NOC/c) by Health Canada for the following indications: 1) as adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis; 2) as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Although the exact mechanism and magnitude of effects of THC and CBD are not fully understood, CBD has been shown to have analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant, and anti-psychotic activity. This wide variety of effects is likely due to it's complex pharmacological mechanisms. In addition to binding to CB1 and CB2 receptors of the endocannabinoid system, there is evidence that CBD activates 5-HT1A serotonergic and TRPV1–2 vanilloid receptors, antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin and gaminobutyric acid and cellular uptake of anandamide, acts on mitochondria Ca2 stores, blocks low-voltage-activated (T-type) Ca2 channels, stimulates activity of the inhibitory glycine-receptor, and inhibits activity of fatty amide hydrolase (FAAH). •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of action of CBD and THC is not currently fully understood. However, it is known that CBD acts on cannabinoid (CB) receptors of the endocannabinoid system, which are found in numerous areas of the body, including the peripheral and central nervous systems, including the brain. The endocannabinoid system regulates many physiological responses of the body including pain, memory, appetite, and mood. More specifically, CB1 receptors can be found within the pain pathways of the brain and spinal cord where they may affect CBD-induced analgesia and anxiolysis, and CB2 receptors have an effect on immune cells, where they may affect CBD-induced anti-inflammatory processes. CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body. Allosteric regulation of a receptor is achieved through the modulation of the activity of a receptor on a functionally distinct site from the agonist or antagonist binding site. The negative allosteric modulatory effects of CBD are therapeutically important as direct agonists are limited by their psychomimetic effects while direct antagonists are limited by their depressant effects. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following a single buccal administration, maximum plasma concentrations of both CBD and THC typically occur within two to four hours. When administered buccally, blood levels of THC and other cannabinoids are lower compared with inhalation of smoked cannabis. The resultant concentrations in the blood are lower than those obtained by inhaling the same dose because absorption is slower, redistribution into fatty tissues is rapid and additionally some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, a psycho-active metabolite. The CBD component of sublingual Sativex was found to have a Tmax of 1.63hr and a Cmax of 2.50ng/mL, while buccal Sativex was found to have a Tmax of 2.80hr and a Cmax of 3.02ng/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): THC and CBD are metabolized in the liver by a number of cytochrome P450 isoenzymes, including CYP2C9, CYP2C19, CYP2D6 and CYP3A4. They may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream and metabolized via the renal and biliary systems. The main primary metabolite of CBD is 7-hydroxy-cannabidiol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Elimination from plasma is bi-exponential with an initial half-life of one to two hours. The terminal elimination half-lives are of the order of 24 to 36 hours or longer. Sativex is excreted in the urine and faeces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The CBD component of sublingual Sativex was found to have a half life (t1/2) of 1.44hr, while buccal Sativex was found to have a half life (t1/2) of 1.81hr. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Epidiolex, Sativex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): .DELTA.1(2)-TRANS-CANNABIDIOL Cannabidiol •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cannabidiol is an active cannabinoid used as an adjunctive treatment for the management of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome and symptomatic relief of moderate to severe neuropathic pain or other painful conditions, like cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cannabidiol interact? Information: •Drug A: Adalimumab •Drug B: Cannabidiol •Severity: MODERATE •Description: The metabolism of Cannabidiol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): When used in combination with delta-9-tetrahydrocannabinol as the product Sativex, cannabidiol was given a standard marketing authorization (ie. a Notice of Compliance (NOC)) by Health Canada for the following indications: 1) as adjunctive treatment for symptomatic relief of spasticity in adult patients with multiple sclerosis (MS) who have not responded adequately to other therapy and who demonstrate meaningful improvement during an initial trial of therapy; Due to the need for confirmatory studies to verify the clinical benefit coupled with the promising nature of the clinical evidence, Sativex was also given a Notice of Compliance with Conditions (NOC/c) by Health Canada for the following indications: 1) as adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis; 2) as adjunctive analgesic treatment in adult patients with advanced cancer who experience moderate to severe pain during the highest tolerated dose of strong opioid therapy for persistent background pain. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Although the exact mechanism and magnitude of effects of THC and CBD are not fully understood, CBD has been shown to have analgesic, anticonvulsant, muscle relaxant, anxiolytic, neuroprotective, anti-oxidant, and anti-psychotic activity. This wide variety of effects is likely due to it's complex pharmacological mechanisms. In addition to binding to CB1 and CB2 receptors of the endocannabinoid system, there is evidence that CBD activates 5-HT1A serotonergic and TRPV1–2 vanilloid receptors, antagonizes alpha-1 adrenergic and µ-opioid receptors, inhibits synaptosomal uptake of noradrenaline, dopamine, serotonin and gaminobutyric acid and cellular uptake of anandamide, acts on mitochondria Ca2 stores, blocks low-voltage-activated (T-type) Ca2 channels, stimulates activity of the inhibitory glycine-receptor, and inhibits activity of fatty amide hydrolase (FAAH). •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of action of CBD and THC is not currently fully understood. However, it is known that CBD acts on cannabinoid (CB) receptors of the endocannabinoid system, which are found in numerous areas of the body, including the peripheral and central nervous systems, including the brain. The endocannabinoid system regulates many physiological responses of the body including pain, memory, appetite, and mood. More specifically, CB1 receptors can be found within the pain pathways of the brain and spinal cord where they may affect CBD-induced analgesia and anxiolysis, and CB2 receptors have an effect on immune cells, where they may affect CBD-induced anti-inflammatory processes. CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body. Allosteric regulation of a receptor is achieved through the modulation of the activity of a receptor on a functionally distinct site from the agonist or antagonist binding site. The negative allosteric modulatory effects of CBD are therapeutically important as direct agonists are limited by their psychomimetic effects while direct antagonists are limited by their depressant effects. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following a single buccal administration, maximum plasma concentrations of both CBD and THC typically occur within two to four hours. When administered buccally, blood levels of THC and other cannabinoids are lower compared with inhalation of smoked cannabis. The resultant concentrations in the blood are lower than those obtained by inhaling the same dose because absorption is slower, redistribution into fatty tissues is rapid and additionally some of the THC undergoes hepatic first pass metabolism to 11-OH-THC, a psycho-active metabolite. The CBD component of sublingual Sativex was found to have a Tmax of 1.63hr and a Cmax of 2.50ng/mL, while buccal Sativex was found to have a Tmax of 2.80hr and a Cmax of 3.02ng/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Cannabinoids are distributed throughout the body; they are highly lipid soluble and accumulate in fatty tissue. The release of cannabinoids from fatty tissue is responsible for the prolonged terminal elimination half-life. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): THC and CBD are metabolized in the liver by a number of cytochrome P450 isoenzymes, including CYP2C9, CYP2C19, CYP2D6 and CYP3A4. They may be stored for as long as four weeks in the fatty tissues from which they are slowly released at sub-therapeutic levels back into the blood stream and metabolized via the renal and biliary systems. The main primary metabolite of CBD is 7-hydroxy-cannabidiol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Elimination from plasma is bi-exponential with an initial half-life of one to two hours. The terminal elimination half-lives are of the order of 24 to 36 hours or longer. Sativex is excreted in the urine and faeces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The CBD component of sublingual Sativex was found to have a half life (t1/2) of 1.44hr, while buccal Sativex was found to have a half life (t1/2) of 1.81hr. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Epidiolex, Sativex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): .DELTA.1(2)-TRANS-CANNABIDIOL Cannabidiol •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cannabidiol is an active cannabinoid used as an adjunctive treatment for the management of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome and symptomatic relief of moderate to severe neuropathic pain or other painful conditions, like cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Adalimumab and Capecitabine interact?

•Drug A: Adalimumab •Drug B: Capecitabine •Severity: MAJOR •Description: The metabolism of Capecitabine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Capecitabine is indicated as treatment for a variety of cancer types. For colorectal cancer, capecitabine is indicated as a single agent or a component of a combination chemotherapy regiment for the adjuvant treatment of stage III colon cancer and treatment unresectable or metastatic colorectal cancer. It can also be used as a part of a combination chemotherapy perioperative treatment of adult locally advanced rectal cancer. For breast cancer, capecitabine is indicated for advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated or as a regimen with docetaxel after disease progression on prior anthracycline-containing chemotherapy. For gastric, esophageal, or gastroesophageal junction (GEJ) cancer, capecitabine is indicated as a component of a combination chemotherapy treatment for the treatment of adult unresectable or metastatic gastric, esophageal, or GEJ cancer or adult HER2-overexpressing metastatic gastric or GEJ adenocarcinoma who have not received prior treatment for metastatic disease. Finally, for pancreatic cancer, capecitabine is indicated as adjuvant treatment for adult pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Capecitabine is a fluoropyrimidine carbamate belonging to a group of antineoplastic agents called antimetabolites, which kill cancerous cells by interfering with DNA synthesis. It is an orally administered systemic prodrug that has little pharmacologic activity until it is converted to 5-fluorouracil (5-FU) by enzymes that are expressed in higher concentrations in many tumors. Capecitabine was designed specifically to overcome the disadvantages of 5-FU and to mimic the infusional pharmacokinetics of 5-FU without the associated complexity and complications of central venous access and infusion pumps. Particularly, since the enzymes converting 5-FU into active metabolites exist in the gastrointestinal tract, infusion of 5-FU can have gastrointestinal toxicity while also losing efficacy. Since capecitabine can be transported intact across the intestinal mucosa, it can be selectively delivered 5-FU to tumor tissues through enzymatic conversion preferentially inside tumor cells. 5-FU exerts its pharmacological action through the inhibition and interference of 3 main targets: thymidylate synthase, DNA, and RNA, leading through protein synthesis disruption and apoptosis. Population-based exposure-effect analyses demonstrated a positive association between AUC of 5-FU and grade 3-4 hyperbilirubinemia. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Capecitabine is metabolized to 5-fluorouracil in vivo by carboxylesterases, cytidine deaminase, and thymidine phosphorylase/uridine phosphorylase sequentially. 5-fluorouracil is further metabolized through a series of enzymatic reactions into 3 main active metabolites: 5-fluorouridine triphosphate (5-FUTP), 5-fluoro-2’-deoxyuridine monophosphate (5-FdUMP), and 5-fluorodeoxyuridine triphosphate (5-FdUTP).. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate (CH 2 THF), bind to thymidylate synthase (TS) to form a covalently bound ternary complex. TS is an enzyme that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Under normal physiological conditions, dUMP binds to TS first before CH 2 THF, followed by a 1,4 or Michael addition from the pyrimidine C (6)atom to the Cys146 nucleophile. If correctly positioned, dUMP, CH 2 THF, and TS would form a ternary complex to facilitate the donation of the methyl group from CH 2 THF to dUMP. However, the substitution of dUMP with FdUMP results in a new time-dependent TS–FdUMP–CH2THF complex. Since the fluorine group prevents dissociation of FdUMP from the pyrimidine ring, the whole complex is rendered irreversibly deactivated, terming this reaction "suicide inhibition". TS inhibition prevents the conversion of dUMP to dTMP, depleting the pool of dTMP that could be phosphorylated into dTTP to be incorporated as DNA nucleotides. This disrupts the nucleotides balance, particularly the the ATP/dTTP ratio, thus impairing DNA synthesis and repair and causing apoptosis. 5-FdUMP can also be phosphorylated into 5-FdUTP, further increasing the pool of dUTP base to potentially overwhelm the activity of dUTPase. Coupled with the decrease in dTTP, 5-FdUMP, and 5-FdUTP increase the probability of mistakenly incorporating a uracil base into DNA strands in place of thymine. Although this mistake can often be resolved by the nucleotide excision repair enzyme uracil-DNA-glycosylase (UDG), the high (F)dUTP/dTTP ratio would result in re-incorporation of uracil into DNA, leading to a futile cycle of misincorporation, excision, and repair. Repeated base excision repair can result in abasic sites, which can lead to DNA mutagenesis and thus protein miscoding, replication forks collapse, and DNA fragmentation through single or double strand breaks However, several reports have found that the incorporation of uracil in genomic DNA does not significantly affect the cytotoxicity of 5-FU, suggesting that the cytotoxic effect of 5-FU is dominated by the perturbation of RNA through 5-FUTP. Similar to 5-dFUTP, 5-FUTP can be mistakenly incorporated into RNA in place of regular UTP and disrupt regular RNA biology through various mechanisms. 5-FUTP can be incorporated into the spliceosomal U2 snRNA at pseudouridylated sites to prevent further pseudouridylation and thus pre-mrNA splicing. 5-FUTP can also change the structure of U4 and U6 snRNA and reduce the turnover rate of U1 snrNA once incorporated. For tRNA, 5-FUTP can affect tRNA's post-transcriptional RNA modifications activity, particularly by inhbiting pseudouridine synthase through formation of covalent complex. Recently, the effect of 5-FUTP on miRNAs and lncRNA was also observed through profound changes in expression, although the precise mechanism is still unknown. Although the main mechanism of 5-FU cytotoxicity was thought to be attributed to DNA damages, recent reports have shown that the majority of 5-FU pharmacological action is mediated through RNA, since 5-FU is accumulated ~3000- to 15 000-fold more in RNA compared to that of DNA. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%. Following oral administration of capecitabine 1,255 mg/m orally twice daily (the recommended dosage when used as a single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): In colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1, the volume of distribution is calculated to be 186 ± 28 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration dependent. Capecitabine was primarily bound to human albumin (approximately 35%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’-DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolyzed by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following administration of radiolabeled capecitabine, 96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1, the clearance of capecitabine is calculated to be 775 ± 213 mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo. In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2,300 mg/m2/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose. Based on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], XELODA can cause fetal harm when administered to a pregnant woman. Available human data on XELODA use in pregnant women is not sufficient to inform the drug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose of 1,250 mg/m2 twice daily, respectively. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Administer uridine triacetate within 96 hours for management of XELODA overdose. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low–molecular-weight metabolite of the parent compound. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ecansya, Xeloda •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capecitabin Capecitabina Capécitabine Capecitabine Capecitabinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Capecitabine is a nucleoside metabolic inhibitor indicated to treat different gastrointestinal, including pancreatic cancer, and breast cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Capecitabine interact? Information: •Drug A: Adalimumab •Drug B: Capecitabine •Severity: MAJOR •Description: The metabolism of Capecitabine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Capecitabine is indicated as treatment for a variety of cancer types. For colorectal cancer, capecitabine is indicated as a single agent or a component of a combination chemotherapy regiment for the adjuvant treatment of stage III colon cancer and treatment unresectable or metastatic colorectal cancer. It can also be used as a part of a combination chemotherapy perioperative treatment of adult locally advanced rectal cancer. For breast cancer, capecitabine is indicated for advanced or metastatic breast cancer as a single agent if an anthracycline- or taxane-containing chemotherapy is not indicated or as a regimen with docetaxel after disease progression on prior anthracycline-containing chemotherapy. For gastric, esophageal, or gastroesophageal junction (GEJ) cancer, capecitabine is indicated as a component of a combination chemotherapy treatment for the treatment of adult unresectable or metastatic gastric, esophageal, or GEJ cancer or adult HER2-overexpressing metastatic gastric or GEJ adenocarcinoma who have not received prior treatment for metastatic disease. Finally, for pancreatic cancer, capecitabine is indicated as adjuvant treatment for adult pancreatic adenocarcinoma as a component of a combination chemotherapy regimen. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Capecitabine is a fluoropyrimidine carbamate belonging to a group of antineoplastic agents called antimetabolites, which kill cancerous cells by interfering with DNA synthesis. It is an orally administered systemic prodrug that has little pharmacologic activity until it is converted to 5-fluorouracil (5-FU) by enzymes that are expressed in higher concentrations in many tumors. Capecitabine was designed specifically to overcome the disadvantages of 5-FU and to mimic the infusional pharmacokinetics of 5-FU without the associated complexity and complications of central venous access and infusion pumps. Particularly, since the enzymes converting 5-FU into active metabolites exist in the gastrointestinal tract, infusion of 5-FU can have gastrointestinal toxicity while also losing efficacy. Since capecitabine can be transported intact across the intestinal mucosa, it can be selectively delivered 5-FU to tumor tissues through enzymatic conversion preferentially inside tumor cells. 5-FU exerts its pharmacological action through the inhibition and interference of 3 main targets: thymidylate synthase, DNA, and RNA, leading through protein synthesis disruption and apoptosis. Population-based exposure-effect analyses demonstrated a positive association between AUC of 5-FU and grade 3-4 hyperbilirubinemia. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Capecitabine is metabolized to 5-fluorouracil in vivo by carboxylesterases, cytidine deaminase, and thymidine phosphorylase/uridine phosphorylase sequentially. 5-fluorouracil is further metabolized through a series of enzymatic reactions into 3 main active metabolites: 5-fluorouridine triphosphate (5-FUTP), 5-fluoro-2’-deoxyuridine monophosphate (5-FdUMP), and 5-fluorodeoxyuridine triphosphate (5-FdUTP).. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate (CH 2 THF), bind to thymidylate synthase (TS) to form a covalently bound ternary complex. TS is an enzyme that catalyzes the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). Under normal physiological conditions, dUMP binds to TS first before CH 2 THF, followed by a 1,4 or Michael addition from the pyrimidine C (6)atom to the Cys146 nucleophile. If correctly positioned, dUMP, CH 2 THF, and TS would form a ternary complex to facilitate the donation of the methyl group from CH 2 THF to dUMP. However, the substitution of dUMP with FdUMP results in a new time-dependent TS–FdUMP–CH2THF complex. Since the fluorine group prevents dissociation of FdUMP from the pyrimidine ring, the whole complex is rendered irreversibly deactivated, terming this reaction "suicide inhibition". TS inhibition prevents the conversion of dUMP to dTMP, depleting the pool of dTMP that could be phosphorylated into dTTP to be incorporated as DNA nucleotides. This disrupts the nucleotides balance, particularly the the ATP/dTTP ratio, thus impairing DNA synthesis and repair and causing apoptosis. 5-FdUMP can also be phosphorylated into 5-FdUTP, further increasing the pool of dUTP base to potentially overwhelm the activity of dUTPase. Coupled with the decrease in dTTP, 5-FdUMP, and 5-FdUTP increase the probability of mistakenly incorporating a uracil base into DNA strands in place of thymine. Although this mistake can often be resolved by the nucleotide excision repair enzyme uracil-DNA-glycosylase (UDG), the high (F)dUTP/dTTP ratio would result in re-incorporation of uracil into DNA, leading to a futile cycle of misincorporation, excision, and repair. Repeated base excision repair can result in abasic sites, which can lead to DNA mutagenesis and thus protein miscoding, replication forks collapse, and DNA fragmentation through single or double strand breaks However, several reports have found that the incorporation of uracil in genomic DNA does not significantly affect the cytotoxicity of 5-FU, suggesting that the cytotoxic effect of 5-FU is dominated by the perturbation of RNA through 5-FUTP. Similar to 5-dFUTP, 5-FUTP can be mistakenly incorporated into RNA in place of regular UTP and disrupt regular RNA biology through various mechanisms. 5-FUTP can be incorporated into the spliceosomal U2 snRNA at pseudouridylated sites to prevent further pseudouridylation and thus pre-mrNA splicing. 5-FUTP can also change the structure of U4 and U6 snRNA and reduce the turnover rate of U1 snrNA once incorporated. For tRNA, 5-FUTP can affect tRNA's post-transcriptional RNA modifications activity, particularly by inhbiting pseudouridine synthase through formation of covalent complex. Recently, the effect of 5-FUTP on miRNAs and lncRNA was also observed through profound changes in expression, although the precise mechanism is still unknown. Although the main mechanism of 5-FU cytotoxicity was thought to be attributed to DNA damages, recent reports have shown that the majority of 5-FU pharmacological action is mediated through RNA, since 5-FU is accumulated ~3000- to 15 000-fold more in RNA compared to that of DNA. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The AUC of capecitabine and its metabolite 5’-DFCR increases proportionally over a dosage range of 500 mg/m2/day to 3,500 mg/m2/day (0.2 to 1.4 times the approved recommended dosage). The AUC of capecitabine’s metabolites 5’-DFUR and fluorouracil increased greater than proportional to the dose. The interpatient variability in the Cmax and AUC of fluorouracil was greater than 85%. Following oral administration of capecitabine 1,255 mg/m orally twice daily (the recommended dosage when used as a single agent), the median Tmax of capecitabine and its metabolite fluorouracil was approximately 1.5 hours and 2 hours, respectively. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): In colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1, the volume of distribution is calculated to be 186 ± 28 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of capecitabine and its metabolites is less than 60% and is not concentration dependent. Capecitabine was primarily bound to human albumin (approximately 35%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Capecitabine undergoes metabolism by carboxylesterase and is hydrolyzed to 5’-DFCR. 5’-DFCR is subsequently converted to 5’-DFUR by cytidine deaminase. 5’-DFUR is then hydrolyzed by thymidine phosphorylase (dThdPase) enzymes to the active metabolite fluorouracil. Fluorouracil is subsequently metabolized by dihydropyrimidine dehydrogenase to 5-fluoro-5, 6-dihydro-fluorouracil (FUH2). The pyrimidine ring of FUH2 is cleaved by dihydropyrimidinase to yield 5-fluoro-ureido-propionic acid (FUPA). Finally, FUPA is cleaved by β-ureido-propionase to α-fluoro-β-alanine (FBAL). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following administration of radiolabeled capecitabine, 96% of the administered capecitabine dose was recovered in urine (3% unchanged and 57% as metabolite FBAL) and 2.6% in feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-lives of capecitabine and fluorouracil were approximately 0.75 hour. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In colorectal cancer patients with a mean age of 58 ± 9.5 years and ECOG Performance Status of 0–1, the clearance of capecitabine is calculated to be 775 ± 213 mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Adequate studies investigating the carcinogenic potential of capecitabine have not been conducted. Capecitabine was not mutagenic in vitro to bacteria (Ames test) or mammalian cells (Chinese hamster V79/HPRT gene mutation assay). Capecitabine was clastogenic in vitro to human peripheral blood lymphocytes but not clastogenic in vivo to mouse bone marrow (micronucleus test). Fluorouracil causes mutations in bacteria and yeast. Fluorouracil also causes chromosomal abnormalities in the mouse micronucleus test in vivo. In studies of fertility and general reproductive performance in female mice, oral capecitabine doses of 760 mg/kg/day (about 2,300 mg/m2/day) disturbed estrus and consequently caused a decrease in fertility. In mice that became pregnant, no fetuses survived this dose. The disturbance in estrus was reversible. In males, this dose caused degenerative changes in the testes, including decreases in the number of spermatocytes and spermatids. In separate pharmacokinetic studies, this dose in mice produced 5’-DFUR AUC values about 0.7 times the corresponding values in patients administered the recommended daily dose. Based on findings in animal reproduction studies and its mechanism of action [see Clinical Pharmacology (12.1)], XELODA can cause fetal harm when administered to a pregnant woman. Available human data on XELODA use in pregnant women is not sufficient to inform the drug-associated risk. In animal reproduction studies, administration of capecitabine to pregnant animals during the period of organogenesis caused embryo lethality and teratogenicity in mice and embryo lethality in monkeys at 0.2 and 0.6 times the exposure (AUC) in patients receiving the recommended dose of 1,250 mg/m2 twice daily, respectively. Advise pregnant women of the potential risk to a fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Administer uridine triacetate within 96 hours for management of XELODA overdose. Although no clinical experience using dialysis as a treatment for XELODA overdose has been reported, dialysis may be of benefit in reducing circulating concentrations of 5’-DFUR, a low–molecular-weight metabolite of the parent compound. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ecansya, Xeloda •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capecitabin Capecitabina Capécitabine Capecitabine Capecitabinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Capecitabine is a nucleoside metabolic inhibitor indicated to treat different gastrointestinal, including pancreatic cancer, and breast cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Caplacizumab interact?

•Drug A: Adalimumab •Drug B: Caplacizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Caplacizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Capacizumab is approved for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP) in conjunction with plasma exchange and immunosuppression in patients 18 years or older. aTTP is a rare autoimmune condition presented by a disruption of blood clotting order which is translated into systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia and organ ischemia. It is caused by the production of autoantibodies against ADAMTS-13 which is the protein in charge of cleaving the von-Wilebrand factor. The lack of this process produces the generation of ultra large von Wilebrand multimers that bind to platelets and form microthrombi and causing thromboembolic complications. Previously, capacizumab was under review for the prevention of thrombosis in high-risk patients with acute coronary syndrome undergoing percutaneous coronary intervention but this indication was withdrawn. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In vitro studies have shown a caplacizumab-driven complete inhibition of platelet aggregation and in phase II clinical trials, it was shown to reduce the activity of the von Willebrand factor by 20% from treatment day 1 until treatment day 30. The level of von Willebrand factor in the plasma was also significantly reduced due to the clearance of the von Willebrand-caplacizumab complex. In phase III clinical trials, more than 50% of the tested individuals reached a platelet normal count. In these trials, it was observed as well a significant reduction in the incidence of aTTP as well as a significant reduction in the median time to response of about 39%. However, as caplacizumab does not target autoimmune response, relapses were observed after treatment discontinuation. The last clinical trial prior approval showed production of a platelet count of more than 150,000 per mcl after the cessation of plasma exchange therapy for 5 days as well as a reduction of patient recurrent thrombotic thrombocytopenic purpura and of disease-related death during treatment. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Caplacizumab acts by targetting the A1 domain of the ultra-large von Willebrand factor which in order inhibits the interaction with the glycoprotein Ib-IX-V receptor in the platelets. Caplacizumab binds to von Willebrand factor with an affinity of 8.5 nM, thus it is very target specific.[5305] The blockage of the von Willebrand factor prevents the interaction between the von Willebrand factor and the platelets, hence, preventing platelet aggregation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After intravenous administration of caplacizumab, the pharmacokinetic profile is non-linear and to follow a non-compartmental model as the pharmacokinetic profile of this drug is dependent on the expression of von Willebrand factor. After administration, caplacizumab is rapidly absorbed with a dose-dependent behavior. The peak concentration was reached after 6-7 hours and it presents a very high bioavailability reaching approximately 90%. The subcutaneous administration of a dose of 10 mg of caplacizumab produced a peak concentration of 528 ng/ml and an AUC of 7951 ng.h/ml. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The reported volume of distribution of caplacizumab is 6.33 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This antibody acts directly on plasma proteins and thus, this parameter is not significant for drug description. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Caplacizumab is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of caplacizumab is divided between target-driven disposition which is driven by the binding to the von Willebrand factor and non-target disposition driven by the combination of catabolism and renal elimination. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The reported half-life is reported to be in the range of 16-27 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): As the elimination is highly divided among hepatic, target-driven and renal elimination, the calculation of the clearance rate is not significant for drug description. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Cases of overdose are represented by an increased risk of bleeding and in these cases, external administration of von Willebrand factor concentrate should be done. To this point, there have not been performed studies regarding the effect on fertility, genotoxicity, or carcinogenicity •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cablivi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment used to treat acquired thrombotic thrombocytopenic purpura (aTTP).

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Caplacizumab interact? Information: •Drug A: Adalimumab •Drug B: Caplacizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Caplacizumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Capacizumab is approved for the treatment of adults experiencing an episode of acquired thrombotic thrombocytopenic purpura (aTTP) in conjunction with plasma exchange and immunosuppression in patients 18 years or older. aTTP is a rare autoimmune condition presented by a disruption of blood clotting order which is translated into systemic microvascular thrombosis leading to profound thrombocytopenia, hemolytic anemia and organ ischemia. It is caused by the production of autoantibodies against ADAMTS-13 which is the protein in charge of cleaving the von-Wilebrand factor. The lack of this process produces the generation of ultra large von Wilebrand multimers that bind to platelets and form microthrombi and causing thromboembolic complications. Previously, capacizumab was under review for the prevention of thrombosis in high-risk patients with acute coronary syndrome undergoing percutaneous coronary intervention but this indication was withdrawn. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In vitro studies have shown a caplacizumab-driven complete inhibition of platelet aggregation and in phase II clinical trials, it was shown to reduce the activity of the von Willebrand factor by 20% from treatment day 1 until treatment day 30. The level of von Willebrand factor in the plasma was also significantly reduced due to the clearance of the von Willebrand-caplacizumab complex. In phase III clinical trials, more than 50% of the tested individuals reached a platelet normal count. In these trials, it was observed as well a significant reduction in the incidence of aTTP as well as a significant reduction in the median time to response of about 39%. However, as caplacizumab does not target autoimmune response, relapses were observed after treatment discontinuation. The last clinical trial prior approval showed production of a platelet count of more than 150,000 per mcl after the cessation of plasma exchange therapy for 5 days as well as a reduction of patient recurrent thrombotic thrombocytopenic purpura and of disease-related death during treatment. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Caplacizumab acts by targetting the A1 domain of the ultra-large von Willebrand factor which in order inhibits the interaction with the glycoprotein Ib-IX-V receptor in the platelets. Caplacizumab binds to von Willebrand factor with an affinity of 8.5 nM, thus it is very target specific.[5305] The blockage of the von Willebrand factor prevents the interaction between the von Willebrand factor and the platelets, hence, preventing platelet aggregation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After intravenous administration of caplacizumab, the pharmacokinetic profile is non-linear and to follow a non-compartmental model as the pharmacokinetic profile of this drug is dependent on the expression of von Willebrand factor. After administration, caplacizumab is rapidly absorbed with a dose-dependent behavior. The peak concentration was reached after 6-7 hours and it presents a very high bioavailability reaching approximately 90%. The subcutaneous administration of a dose of 10 mg of caplacizumab produced a peak concentration of 528 ng/ml and an AUC of 7951 ng.h/ml. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The reported volume of distribution of caplacizumab is 6.33 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): This antibody acts directly on plasma proteins and thus, this parameter is not significant for drug description. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Caplacizumab is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of caplacizumab is divided between target-driven disposition which is driven by the binding to the von Willebrand factor and non-target disposition driven by the combination of catabolism and renal elimination. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The reported half-life is reported to be in the range of 16-27 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): As the elimination is highly divided among hepatic, target-driven and renal elimination, the calculation of the clearance rate is not significant for drug description. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Cases of overdose are represented by an increased risk of bleeding and in these cases, external administration of von Willebrand factor concentrate should be done. To this point, there have not been performed studies regarding the effect on fertility, genotoxicity, or carcinogenicity •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cablivi •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Caplacizumab is a von Willebrand factor (vWF)-directed antibody fragment used to treat acquired thrombotic thrombocytopenic purpura (aTTP). Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Capsaicin interact?

•Drug A: Adalimumab •Drug B: Capsaicin •Severity: MODERATE •Description: The metabolism of Capsaicin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal. The peak blood concentration can be reached within 1 hour following administration. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26.6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2.47 ± 0.13 ng/ml was reached at 47.1 ± 2.0 minutes. Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood. Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL but the maximum value observed in any patient was 17.8 ng/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following oral ingestion of equipotent dose of 26.6 mg of pure capsaicin, the half life was approximately 24.9 ± 5.0 min. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h. The mean population elimination half-life was 1.64 h following application of a topical patch containing 179 mg of capsaicin. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Acute oral LD50 and dermal LD50 in mouse are 47.2 mg/kg and >512 mg/kg, respectively. Capsaicin is shown to be mutagenic for bacteria and yeast. Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Capzasin Quick Relief, Capzasin-HP, Castiva Warming, Dendracin Neurodendraxcin, Lidopro, Medi-derm, Medi-derm With Lidocaine, Medrox, Qutenza, Rematex, Xoten-C, Zostrix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capsaicin Capsaicina Isodecenoic acid vanillylamide •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Capsaicin is a topical analgesic agent used for the symptomatic relief of neuropathic pain associated with post-herpetic neuralgia, as well as other muscle and joint pain.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Capsaicin interact? Information: •Drug A: Adalimumab •Drug B: Capsaicin •Severity: MODERATE •Description: The metabolism of Capsaicin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): The capsaicin 8% patch is indicated in the treatment of neuropathic pain associated with post-herpetic neuralgia. There are multiple topical capsaicin formulations available, including creams and solutions, indicated for temporary analgesia in muscle and join pain as well as neuropathic pain. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Capsaicin is a TRPV1 receptor agonist. TRPV1 is a trans-membrane receptor-ion channel complex activated by temperatures higher than 43 degrees Celsius, pH lower than 6, and endogenous lipids. When activated by a combination of these factors, the channel can transiently open and initiate depolarization due to the influx of calcium and sodium ions. Because TRPV1 is commonly expressed in A-delta and mostly C fibers, depolarization results in action potentials which send impulses to the brain and spinal cord. These impulses result in capsaicin effects of warming, tingling, itching, stinging, or burning. Capsaicin also causes more persistent activation of these receptors compared to the environmental agonists, resulting in a loss of response to many sensory stimuli, described as "defunctionalization". Capsaicin is associated with many enzymatic, cytoskeletal, and osmotic changes, as well as disruption of mitochondrial respiration, impairing nociceptor function for extended periods of time. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Capsaicin has been shown to reduce the amount of substance P associated with inflammation - however this is not believed to be its main mechanism in the relief of pain. Capsaicin's mechanism of action is attributed to "defunctionalization" of nociceptor fibers by inducing a topical hypersensitivity reaction on the skin. This alteration in pain mechanisms is due to many of the following: temporary loss of membrane potential, inability to transport neurotrophic factors leading to altered phenotype, and reversible retraction of epidermal and dermal nerve fiber terminals. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Oral: Following oral administration, capsaicin may be absorbed by a nonactive process from the stomach and whole intestine with an extent of absorption ranging between 50 and 90%, depending on the animal. The peak blood concentration can be reached within 1 hour following administration. Capsaicin may undergo minor metabolism in the small intestine epithelial cells post-absorption from the stomach into the small intestines. While oral pharmacokinetics information in humans is limited, ingestion of equipotent dose of 26.6 mg of pure capsaicin, capsaicin was detected in the plasma after 10 minutes and the peak plasma concentration of 2.47 ± 0.13 ng/ml was reached at 47.1 ± 2.0 minutes. Systemic: Following intravenous or subcutaneous administration in animals, the concentrations in the brain and spinal cord were approximately 5-fold higher than that in blood and the concentration in the liver was approximately 3-fold higher than that in blood. Topical: Topical capsaicin in humans is rapidly and well absorbed through the skin, however systemic absorption following topical or transdermal administration is unlikely. For patients receiving the topical patch containing 179 mg of capsaicin, a population analysis was performed and plasma concentrations of capsaicin were fitted using a one-compartment model with first-order absorption and linear elimination. The mean peak plasma concentration was 1.86 ng/mL but the maximum value observed in any patient was 17.8 ng/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Capsaicin metabolism after oral administration is unclear, however it is expected to undergo metabolism in the liver with minimal metabolism in the gut lumen. In vitro studies with human hepatic microsomes and S9 fragments indicate that capsaicin is rapidly metabolized, producing three major metabolites, 16-hydroxycapsaicin, 17-hydroxycapsaicin, and 16,17-hydroxycapsaicin, whereas vanillin was a minor metabolite. It is proposed that cytochrome P450 (P450) enzymes may play some role in hepatic drug metabolism. In vitro studies of capsaicin in human skin suggest slow biotransformation with most capsaicin remaining unchanged. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): It is proposed that capsaicin mainly undergoes renal excretion, as both the unchanged and glucuronide form. A small fraction of unchanged compound is excreted in the feces and urine. In vivo animal studies demonstrates that less than 10 % of an administered dose was found in faces after 48 h. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following oral ingestion of equipotent dose of 26.6 mg of pure capsaicin, the half life was approximately 24.9 ± 5.0 min. Following topical application of 3% solution of capsaicin, the half-life of capsaicin was approximately 24 h. The mean population elimination half-life was 1.64 h following application of a topical patch containing 179 mg of capsaicin. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Acute oral LD50 and dermal LD50 in mouse are 47.2 mg/kg and >512 mg/kg, respectively. Capsaicin is shown to be mutagenic for bacteria and yeast. Capsaicin can cause serious irritation, conjunctivitis and lacrimation via contact with eyes. It induces a burning sensation and pain in case of contact with eyes and skin. As it is also irritating to the respiratory system, it causes lung irritation and coughing as well as bronchoconstriction. Other respiratory effects include laryngospasm, swelling of the larynx and lungs, chemical pneumonitis,respiratory arrest and central nervous system effects such as convulsions and excitement. In case of ingestion, gastrointestinal tract irritation may be observed along with a sensation of warmth or painful burning. Symptoms of systemic toxicity include disorientation, fear, loss of body motor control including diminished hand-eye coordination, hyperventilation, tachycardia, and pulmonary oedema. Careful early decontamination is recommended and medical intervention should be initiated for any life-threatening symptoms. In case of contact, individual must be removed from the source of exposure and the contacted skin and mucous membranes should be thoroughly washed with copious amounts of water. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Capzasin Quick Relief, Capzasin-HP, Castiva Warming, Dendracin Neurodendraxcin, Lidopro, Medi-derm, Medi-derm With Lidocaine, Medrox, Qutenza, Rematex, Xoten-C, Zostrix •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Capsaicin Capsaicina Isodecenoic acid vanillylamide •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Capsaicin is a topical analgesic agent used for the symptomatic relief of neuropathic pain associated with post-herpetic neuralgia, as well as other muscle and joint pain. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Carbamazepine interact?

•Drug A: Adalimumab •Drug B: Carbamazepine •Severity: MAJOR •Description: The metabolism of Carbamazepine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carbamazepine is indicated for the treatment of epilepsy and pain associated with true trigeminal neuralgia. In particular, carbamazepine has shown efficacy in treating mixed seizures, partial seizures with complex symptoms, and generalized tonic-clonic seizures. Carbamazepine is also indicated for the treatment of manic episodes and mixed manic-depressive episodes caused by bipolar I disorder. Some off-label, unapproved uses of carbamazepine include the treatment of alcohol withdrawal syndrome and restless leg syndrome. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): General effects Carbamazepine treats seizures and the symptoms of trigeminal neuralgia by inhibiting sodium channels. In bipolar 1 disorder, carbamazepine has been found to decrease mania symptoms in a clinically significant manner according to the Young Mania Rating Scale (YMRS). Carbamazepine has a narrow therapeutic index. A note on genetic variation and carbamazepine use In studies of Han Chinese ancestry patients, a pronounced association between the HLA-B*1502 genotype and Steven Johnson syndrome and/or toxic epidermal necrolysis (SJS/TEN) resulting from carbamazepine use was observed. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carbamazepine's mechanism of action is not fully elucidated and is widely debated. One major hypothesis is that carbamazepine inhibits sodium channel firing, treating seizure activity. Animal research studies have demonstrated that carbamazepine exerts its effects by lowering polysynaptic nerve response and inhibiting post-tetanic potentiation. In both cats and rats, carbamazepine was shown to decrease pain caused by infraorbital nerve stimulation. A decrease in the action potential in the nucleus ventralis of the thalamus in the brain and inhibition of the lingual mandibular reflex were observed in other studies after carbamazepine use. Carbamazepine causes the above effects by binding to voltage-dependent sodium channels and preventing action potentials, which normally lead to stimulatory effects on nerves. In bipolar disorder, carbamazepine is thought to increase dopamine turnover and increase GABA transmission, treating manic and depressive symptoms. A common issue that has arisen is resistance to this drug in up to 30% of epileptic patients, which may occur to altered metabolism in patients with variant genotypes. A potential therapeutic target to combat carbamazepine resistance has recently been identified as the EPHX1 gene promoter, potentially conferring resistance to carbamazepine through methylation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose. After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1.9 ± 0.3 mcg/mL. The Tmax was 19 ± 7 hours. After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11.0 ± 2.5 mcg/mL. The Tmax was reduced to 5.9 ± 1.8 hours. Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg. Effect of food on absorption A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine. The elimination half-life remained unchanged between fed and fasting state. The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food. Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of carbamazepine was found to be 1.0 L/kg in one pharmacokinetic study. Another study indicates that the volume of distribution of carbamazepine ranges between 0.7 to 1.4 L/kg.. Carbamazepine crosses the placenta, and higher concentrations of this drug are found in the liver and kidney as opposed to lung and brain tissue. Carbamazepine crosses variably through the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Carbamazepine is 75%-80% bound to plasma proteins. One pharmacokinetic study indicates that it is 72% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carbamazepine is largely metabolized in the liver. CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase. Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6. Carbamazepine also undergoes hepatic glucuronidation by UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites. Interestingly, carbamazepine induces its own metabolism. This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After an oral dose of radiolabeled carbamazepine, 72% of the administered radioactive dose was detected in the urine and the remainder of the ingested dose was found in the feces. Carbamazepine is mainly excreted as hydroxylated and conjugated metabolites, and minimal amounts of unchanged drug. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean elimination half-life of carbamazepine was 35 to 40 hours after one dose of carbamazepine extended-release formulations. The half-life ranged from 12-17 hours after several doses of carbamazepine. One pharmacokinetic study determined the elimination half-life of carbamazepine to range between 27 to 36.8 hours in healthy volunteers. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In a pharmacokinetic study, the apparent oral clearance of carbamazepine was 25 ± 5 mL/min after one dose of carbamazepine and 80 ± 30 mL/min after several doses. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Toxicity information Oral LDLO (female): 1920 mg/kg/17W (intermittent); Oral LDLO (male): 54 mg/kg/9D (intermittent) Oral LD50 (rat): 1957 mg/kg Overdose information The initial signs of carbamazepine overdose occur 1-3 hours post ingestion. These signs and symptoms may vary in case of an overdose between carbamazepine and other drugs. Carbamazepine may cause various cardiovascular, neurological, respiratory, urinary symptoms as well as laboratory abnormalities including leukocytosis, reduced leucocytes, acetonuria, and glycosuria. Neuromuscular symptoms may occur initially, followed by mild cardiac symptoms such as tachycardia, hypertension, or hypotension. Higher doses of carbamazepine may cause more severed cardiovascular effects. Restlessness, muscular twitching, tremor, dilated pupils, nystagmus, psychomotor disturbances, and other neurological symptoms may occur. Hyperreflexia in the initial stages of overdose may be followed by hyporeflexia. Nausea, vomiting, urinary retention, dizziness or drowsiness may also occur. In cases of overdose, contact the local poison control center. Ensure to provide supportive and symptomatic treatment, which may include monitoring and careful supervision by a medical professional. The possibility of overdose with multiple drugs must be considered in the case of carbamazepine overdose. Maintain an adequate airway, oxygen, in addition to ventilation. Vital signs should be monitored. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Carbatrol, Carnexiv, Epitol, Equetro, Tegretol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carbamazepen Carbamazepin Carbamazepina Carbamazépine Carbamazepine Carbamazepinum Molecusol-Carbamazepine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carbamazepine is an anticonvulsant used to treat various types of seizures and pain resulting from trigeminal neuralgia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Carbamazepine interact? Information: •Drug A: Adalimumab •Drug B: Carbamazepine •Severity: MAJOR •Description: The metabolism of Carbamazepine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carbamazepine is indicated for the treatment of epilepsy and pain associated with true trigeminal neuralgia. In particular, carbamazepine has shown efficacy in treating mixed seizures, partial seizures with complex symptoms, and generalized tonic-clonic seizures. Carbamazepine is also indicated for the treatment of manic episodes and mixed manic-depressive episodes caused by bipolar I disorder. Some off-label, unapproved uses of carbamazepine include the treatment of alcohol withdrawal syndrome and restless leg syndrome. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): General effects Carbamazepine treats seizures and the symptoms of trigeminal neuralgia by inhibiting sodium channels. In bipolar 1 disorder, carbamazepine has been found to decrease mania symptoms in a clinically significant manner according to the Young Mania Rating Scale (YMRS). Carbamazepine has a narrow therapeutic index. A note on genetic variation and carbamazepine use In studies of Han Chinese ancestry patients, a pronounced association between the HLA-B*1502 genotype and Steven Johnson syndrome and/or toxic epidermal necrolysis (SJS/TEN) resulting from carbamazepine use was observed. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carbamazepine's mechanism of action is not fully elucidated and is widely debated. One major hypothesis is that carbamazepine inhibits sodium channel firing, treating seizure activity. Animal research studies have demonstrated that carbamazepine exerts its effects by lowering polysynaptic nerve response and inhibiting post-tetanic potentiation. In both cats and rats, carbamazepine was shown to decrease pain caused by infraorbital nerve stimulation. A decrease in the action potential in the nucleus ventralis of the thalamus in the brain and inhibition of the lingual mandibular reflex were observed in other studies after carbamazepine use. Carbamazepine causes the above effects by binding to voltage-dependent sodium channels and preventing action potentials, which normally lead to stimulatory effects on nerves. In bipolar disorder, carbamazepine is thought to increase dopamine turnover and increase GABA transmission, treating manic and depressive symptoms. A common issue that has arisen is resistance to this drug in up to 30% of epileptic patients, which may occur to altered metabolism in patients with variant genotypes. A potential therapeutic target to combat carbamazepine resistance has recently been identified as the EPHX1 gene promoter, potentially conferring resistance to carbamazepine through methylation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The bioavailability of carbamazepine is in the range of 75-85% of an ingested dose. After one 200 mg oral extended-release dose of carbamazepine in a pharmacokinetic study, the Cmax carbamazepine was measured to be 1.9 ± 0.3 mcg/mL. The Tmax was 19 ± 7 hours. After several doses of 800 mg every 12 hours, the peak concentrations of carbamazepine were measured to be 11.0 ± 2.5 mcg/mL. The Tmax was reduced to 5.9 ± 1.8 hours. Extended-release carbamazepine demonstrated linear pharmacokinetics over a range of 200–800 mg. Effect of food on absorption A meal containing high-fat content increased the rate of absorption of one 400 mg dose but not the AUC of carbamazepine. The elimination half-life remained unchanged between fed and fasting state. The pharmacokinetics of an extended-release carbamazepine dose was demonstrated to be similar when administered in the fasted state or with food. Based on these findings, food intake is unlikely to exert significant effects on carbamazepine absorption. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of carbamazepine was found to be 1.0 L/kg in one pharmacokinetic study. Another study indicates that the volume of distribution of carbamazepine ranges between 0.7 to 1.4 L/kg.. Carbamazepine crosses the placenta, and higher concentrations of this drug are found in the liver and kidney as opposed to lung and brain tissue. Carbamazepine crosses variably through the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Carbamazepine is 75%-80% bound to plasma proteins. One pharmacokinetic study indicates that it is 72% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carbamazepine is largely metabolized in the liver. CYP3A4 hepatic enzyme is the major enzyme that metabolizes carbamazepine to its active metabolite, carbamazepine-10,11-epoxide, which is further metabolized to its trans-diol form by the enzyme epoxide hydrolase. Other hepatic cytochrome enzymes that contribute to the metabolism of carbamazepine are CYP2C8, CYP3A5, and CYP2B6. Carbamazepine also undergoes hepatic glucuronidation by UGT2B7 enzyme and several other metabolic reactions occur, resulting in the formation of minor hydroxy metabolites and quinone metabolites. Interestingly, carbamazepine induces its own metabolism. This leads to enhanced clearance, reduced half-life, and a reduction in serum levels of carbamazepine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After an oral dose of radiolabeled carbamazepine, 72% of the administered radioactive dose was detected in the urine and the remainder of the ingested dose was found in the feces. Carbamazepine is mainly excreted as hydroxylated and conjugated metabolites, and minimal amounts of unchanged drug. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean elimination half-life of carbamazepine was 35 to 40 hours after one dose of carbamazepine extended-release formulations. The half-life ranged from 12-17 hours after several doses of carbamazepine. One pharmacokinetic study determined the elimination half-life of carbamazepine to range between 27 to 36.8 hours in healthy volunteers. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In a pharmacokinetic study, the apparent oral clearance of carbamazepine was 25 ± 5 mL/min after one dose of carbamazepine and 80 ± 30 mL/min after several doses. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Toxicity information Oral LDLO (female): 1920 mg/kg/17W (intermittent); Oral LDLO (male): 54 mg/kg/9D (intermittent) Oral LD50 (rat): 1957 mg/kg Overdose information The initial signs of carbamazepine overdose occur 1-3 hours post ingestion. These signs and symptoms may vary in case of an overdose between carbamazepine and other drugs. Carbamazepine may cause various cardiovascular, neurological, respiratory, urinary symptoms as well as laboratory abnormalities including leukocytosis, reduced leucocytes, acetonuria, and glycosuria. Neuromuscular symptoms may occur initially, followed by mild cardiac symptoms such as tachycardia, hypertension, or hypotension. Higher doses of carbamazepine may cause more severed cardiovascular effects. Restlessness, muscular twitching, tremor, dilated pupils, nystagmus, psychomotor disturbances, and other neurological symptoms may occur. Hyperreflexia in the initial stages of overdose may be followed by hyporeflexia. Nausea, vomiting, urinary retention, dizziness or drowsiness may also occur. In cases of overdose, contact the local poison control center. Ensure to provide supportive and symptomatic treatment, which may include monitoring and careful supervision by a medical professional. The possibility of overdose with multiple drugs must be considered in the case of carbamazepine overdose. Maintain an adequate airway, oxygen, in addition to ventilation. Vital signs should be monitored. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Carbatrol, Carnexiv, Epitol, Equetro, Tegretol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carbamazepen Carbamazepin Carbamazepina Carbamazépine Carbamazepine Carbamazepinum Molecusol-Carbamazepine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carbamazepine is an anticonvulsant used to treat various types of seizures and pain resulting from trigeminal neuralgia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Carboplatin interact?

•Drug A: Adalimumab •Drug B: Carboplatin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Carboplatin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carboplatin is indicated in combination with an established combination of chemotherapeutic agents for the initial treatment of advanced ovarian carcinoma. Carboplatin is also indicated for the palliative treatment of ovarian carcinoma, recurrent after prior chemotherapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carboplatin is an organoplatinum antineoplastic alkylating agent used in the treatment of advanced ovarian carcinoma. Carboplatin has a long duration of action as it is given every 4 weeks, and a narrow therapeutic index. Patients should be counselled regarding bone marrow suppression and anemia. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carboplatin predominantly acts by attaching alkyl groups to the nucleotides, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error. 2% of carboplatin's activity comes from DNA cross-linking from a base on one strand to a base on another, preventing DNA strands from separating for synthesis or transcription. Finally, carboplatin can induce a number of different mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The C max and AUC of carboplatin increase proportionally with increasing doses. A 75 mg/m dose reaches a C max of 9.06 ± 0.74 µg/mL, with an AUC of 27.18 ± 11.28 h*µg/mL. A 450 mg/m dose reaches a C max of 55.39 ± 18.30 µg/mL, with an AUC of 224.41 ± 69.07 h*µg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution after a 30 minute intravenous infusion of 300-500 mg/m was 16 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Carboplatin is not bound to plasma protein. However, the free platinum is 40% irreversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carboplatin is predominantly eliminated as the unchanged parent compound. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Carboplatin is 65% eliminated in the urine within 12 hours, and 71% eliminated within 24 hours. An additional 3-5% is eliminated in urine from 24 hours to 96 hours. Biliary elimination has not been determined. Carboplatin is predominantly eliminated as the unchanged parent compound. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The distribution half life of carboplatin is 1.1-2 hours, and the elimination half life was2.6-5.9 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The total body clearance after a 30 minute intravenous infusion of 300-500 mg/m was 4.4 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Patients experiencing an overdose of carboplatin may present with pronounced neutropenia and hepatotoxicity. Treat patients with symptomatic and supportive measures, which may include delaying their next treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Paraplatin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carboplatin Carboplatine Carboplatino CBDCA •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carboplatin is a alkylating agent used to treat advanced ovarian cancer.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Carboplatin interact? Information: •Drug A: Adalimumab •Drug B: Carboplatin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Carboplatin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carboplatin is indicated in combination with an established combination of chemotherapeutic agents for the initial treatment of advanced ovarian carcinoma. Carboplatin is also indicated for the palliative treatment of ovarian carcinoma, recurrent after prior chemotherapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carboplatin is an organoplatinum antineoplastic alkylating agent used in the treatment of advanced ovarian carcinoma. Carboplatin has a long duration of action as it is given every 4 weeks, and a narrow therapeutic index. Patients should be counselled regarding bone marrow suppression and anemia. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carboplatin predominantly acts by attaching alkyl groups to the nucleotides, leading to the formation of monoadducts, and DNA fragmenting when repair enzymes attempt to correct the error. 2% of carboplatin's activity comes from DNA cross-linking from a base on one strand to a base on another, preventing DNA strands from separating for synthesis or transcription. Finally, carboplatin can induce a number of different mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The C max and AUC of carboplatin increase proportionally with increasing doses. A 75 mg/m dose reaches a C max of 9.06 ± 0.74 µg/mL, with an AUC of 27.18 ± 11.28 h*µg/mL. A 450 mg/m dose reaches a C max of 55.39 ± 18.30 µg/mL, with an AUC of 224.41 ± 69.07 h*µg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution after a 30 minute intravenous infusion of 300-500 mg/m was 16 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Carboplatin is not bound to plasma protein. However, the free platinum is 40% irreversibly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carboplatin is predominantly eliminated as the unchanged parent compound. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Carboplatin is 65% eliminated in the urine within 12 hours, and 71% eliminated within 24 hours. An additional 3-5% is eliminated in urine from 24 hours to 96 hours. Biliary elimination has not been determined. Carboplatin is predominantly eliminated as the unchanged parent compound. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The distribution half life of carboplatin is 1.1-2 hours, and the elimination half life was2.6-5.9 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The total body clearance after a 30 minute intravenous infusion of 300-500 mg/m was 4.4 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Patients experiencing an overdose of carboplatin may present with pronounced neutropenia and hepatotoxicity. Treat patients with symptomatic and supportive measures, which may include delaying their next treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Paraplatin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carboplatin Carboplatine Carboplatino CBDCA •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carboplatin is a alkylating agent used to treat advanced ovarian cancer. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Carfilzomib interact?

•Drug A: Adalimumab •Drug B: Carfilzomib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Carfilzomib. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carfilzomib is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with lenalidomide and dexamethasone; or dexamethasone; or daratumumab and dexamethasone; or daratumumab and hyaluronidase-fihj and dexamethasone; or isatuximab and dexamethasone. It is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. Resistance against carfilzomib has been observed and although the mechanism has not been confirmed, it is thought that up-regulation of P-glycoprotein may be a contributing factor. Furthermore, studies suggest that carfilzomib is more potent than bortezomib. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carfilzomib is made up of four modified peptides and acts as a proteasome inhibitor. Carfilzomib irreversibly and selectively binds to N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. This 20S core has 3 catalytic active sites: the chymotrypsin, trypsin, and caspase-like sites. Inhibition of the chymotrypsin-like site by carfilzomib (β5 and β5i subunits) is the most effective target in decreasing cellular proliferation, ultimately resulting in cell cycle arrest and apoptosis of cancerous cells. At higher doses, carfilzomib will inhibit the trypsin-and capase-like sites. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cmax, single IV dose of 27 mg/m^2 = 4232 ng/mL; AUC, single IV dose of 27 mg/m^2 = 379 ng•hr/mL; Carfilzomib does not accumulation in the systemic. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Vd, steady state, 20 mg/m^2 = 28 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Over the concentration range of 0.4 - 4 micromolar, carfilzomib was 97% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carfilzomib was rapidly and extensively metabolized by the liver. The predominant metabolites were the peptide fragments and the diol of carfilzomib which suggests that the main metabolic pathways are peptidase cleavage and epoxide hydrolysis. The cytochrome P450 enzyme system is minimally involved in the metabolism of carfilzomib. All metabolites are inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following intravenous administration of doses ≥ 15 mg/m^2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Systemic clearance = 151 - 263 L/hour. As this value exceeds hepatic blood flow, it suggests that carfilozmib is cleared extrahepatically. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. The two dose limiting toxicities are thrombocytopenia and febrile neutropenia. Maximum tolerate dose = 15 mg/m^2 •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Kyprolis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carfilzomib is a proteasome inhibitor used either alone or in conjunction with a chemotherapy regimen to treat patients with relapsed or refractory multiple myeloma.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Carfilzomib interact? Information: •Drug A: Adalimumab •Drug B: Carfilzomib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Carfilzomib. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carfilzomib is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy in combination with lenalidomide and dexamethasone; or dexamethasone; or daratumumab and dexamethasone; or daratumumab and hyaluronidase-fihj and dexamethasone; or isatuximab and dexamethasone. It is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Intravenous carfilzomib administration resulted in suppression of proteasome chymotrypsin-like activity when measured in blood 1 hour after the first dose. On Day 1 of Cycle 1, proteasome inhibition in peripheral blood mononuclear cells (PBMCs) ranged from 79% to 89% at 15 mg/m2, and from 82% to 83% at 20 mg/m2. In addition, carfilzomib administration resulted in inhibition of the LMP2 and MECL1 subunits of the immunoproteasome ranging from 26% to 32% and 41% to 49%, respectively, at 20 mg/m2. Proteasome inhibition was maintained for ≥ 48 hours following the first dose of carfilzomib for each week of dosing. Resistance against carfilzomib has been observed and although the mechanism has not been confirmed, it is thought that up-regulation of P-glycoprotein may be a contributing factor. Furthermore, studies suggest that carfilzomib is more potent than bortezomib. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carfilzomib is made up of four modified peptides and acts as a proteasome inhibitor. Carfilzomib irreversibly and selectively binds to N-terminal threonine-containing active sites of the 20S proteasome, the proteolytic core particle within the 26S proteasome. This 20S core has 3 catalytic active sites: the chymotrypsin, trypsin, and caspase-like sites. Inhibition of the chymotrypsin-like site by carfilzomib (β5 and β5i subunits) is the most effective target in decreasing cellular proliferation, ultimately resulting in cell cycle arrest and apoptosis of cancerous cells. At higher doses, carfilzomib will inhibit the trypsin-and capase-like sites. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cmax, single IV dose of 27 mg/m^2 = 4232 ng/mL; AUC, single IV dose of 27 mg/m^2 = 379 ng•hr/mL; Carfilzomib does not accumulation in the systemic. At doses between 20 and 36 mg/m2, there was a dose-dependent increase in exposure. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Vd, steady state, 20 mg/m^2 = 28 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Over the concentration range of 0.4 - 4 micromolar, carfilzomib was 97% protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carfilzomib was rapidly and extensively metabolized by the liver. The predominant metabolites were the peptide fragments and the diol of carfilzomib which suggests that the main metabolic pathways are peptidase cleavage and epoxide hydrolysis. The cytochrome P450 enzyme system is minimally involved in the metabolism of carfilzomib. All metabolites are inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following intravenous administration of doses ≥ 15 mg/m^2, carfilzomib was rapidly cleared from the systemic circulation with a half-life of ≤ 1 hour on Day 1 of Cycle 1. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Systemic clearance = 151 - 263 L/hour. As this value exceeds hepatic blood flow, it suggests that carfilozmib is cleared extrahepatically. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Most commonly reported adverse reactions (incidence ≥ 30%) are fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, and pyrexia. The two dose limiting toxicities are thrombocytopenia and febrile neutropenia. Maximum tolerate dose = 15 mg/m^2 •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Kyprolis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carfilzomib is a proteasome inhibitor used either alone or in conjunction with a chemotherapy regimen to treat patients with relapsed or refractory multiple myeloma. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Carisoprodol interact?

•Drug A: Adalimumab •Drug B: Carisoprodol •Severity: MODERATE •Description: The metabolism of Carisoprodol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carisoprodol is indicated for the relief of discomfort related to acute, painful musculoskeletal conditions. Important limitations of use: • Should only be used for acute treatment periods up to two or three weeks • Adequate evidence of effectiveness for more prolonged use has not been established • Not recommended in pediatric patients less than 16 years of age •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carisoprodol is a centrally acting skeletal muscle relaxant that does not act directly on skeletal muscle but acts directly on the central nervous system (CNS). This drug relieves the painful effects of muscle spasm. A metabolite of carisoprodol, meprobamate, possesses both anxiolytic and sedative properties. Clinical studies have shown that this drug causes impairment of psychomotor performance in neuropsychological tests. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been confirmed. In studies using animal models, the muscle relaxation that is induced by carisoprodol is associated with a change in the interneuronal activity of the spinal cord and of the descending reticular formation, located in the brain. The abuse potential of this drug is attributed to its ability to alter GABAA function. This drug has been shown to modulate a variety of GABAA receptor subunits. GABAA receptor modulation can lead to anxiolysis due to inhibitory effects on neurotransmission. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absolute bioavailability of carisoprodol has not yet been established. The mean time to peak plasma concentrations (Tmax) of this drug was about 1.5-2 hours in clinical studies. Co-administration of a fatty meal with carisoprodol (350 mg tablet) had no impact on carisoprodol pharmacokinetics. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.93 to 1.3 L/kg, according to 4 different clinical studies. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 60%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The main pathway of carisoprodol is liver metabolism is by the cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism, which may affect the metabolism of this drug. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Carisoprodol is eliminated by the kidneys as well as other routes. The half-life of meprobamate is approximately 10 hours. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life is approximately 2 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Following an oral dose of carisoprodol, the oral clearance (Cl/F) was 39.52 ± 16.83 L/hour. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): LD50 values The LD50 values of carisoprodol for rats are 450 mg/kg for intravenous (IV) and intraperitoneal injection, and 1,320 mg/kg for gavage dosing. In mice, the LD50 values are 165 mg/kg for intravenous injection, 980 mg/kg for intraperitoneal injection, and 2,340 mg/kg for gavage dosing. The LD50 value for rabbits given carisoprodol by intravenous injection is 124 mg/kg. Overdose An overdose of carisoprodol leads to CNS depression, and in severe cases, induction of a coma. Shock, depression of respiratory function, seizures and death have also been reported in rare cases. Several symptoms may be associated with carisoprodol overdose, such as horizontal and vertical nystagmus, blurred vision, mydriasis, mild tachycardia and hypotension, respiratory depression, euphoria, CNS stimulation, muscular incoordination, and/or rigidity, confusion, headache, hallucinations, and dystonic reactions. Alcohol or other CNS depressants or psychotropic agents can exert additive effects on carisoprodol even when one of the agents has been ingested at the normal, therapeutic dose. Fatal accidental and non-accidental overdoses have both been reported with carisoprodol ingestion alone or ingestion of carisoprodol in combination with alcohol or psychotropic drugs. A note on dependence and withdrawal In the postmarketing reports after carisoprodol use, cases of dependence, withdrawal, and abuse have been reported with long-term use. The majority of dependence and withdrawal cases, as well as abuse, have occurred in patients with a history of addiction or who have used this drug in combination with other drugs having abuse potential. However, multiple post-marketing adverse event reports have been made of carisodopril-associated abuse when used without other drugs possessing abuse potential. Withdrawal symptoms have been observed and reported following sudden abrupt cessation after long-term carisodoprol use. To reduce the chance of carisodopril dependence, withdrawal, or abuse, carisodopril should be used with caution in addiction-prone patients and in patients taking other CNS depressants including alcohol. This drug should not be taken for longer than 2 to 3 weeks for symptomatic relief of acute musculoskeletal discomfort. Use in pregnancy This drug has been classified as Pregnancy Category C. There are no clinical trial data on the use of carisoprodol during human pregnancy. Animal studies show that carisoprodol crosses the placenta and leads to adverse effects on fetal growth and postnatal survival. In postmarketing reports, the main metabolite, meprobamate, has not demonstrated a consistent association between maternal use and an increased risk for specific congenital malformations. Use in nursing Limited data in humans demonstrate that this is found excreted in breast milk and may reach concentrations in breast milk of 2-4 times the maternal plasma concentrations. It is therefore advisable to exercise caution when this drug is used during breastfeeding. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Soma, Vanadom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carisoprodol Carisoprodolo Carisoprodolum Isobamate Isomeprobamate Isopropyl meprobamate Isopropylmeprobamate •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carisoprodol is a centrally acting muscle relaxant used to relieve the discomfort associated with various musculoskeletal conditions.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Carisoprodol interact? Information: •Drug A: Adalimumab •Drug B: Carisoprodol •Severity: MODERATE •Description: The metabolism of Carisoprodol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carisoprodol is indicated for the relief of discomfort related to acute, painful musculoskeletal conditions. Important limitations of use: • Should only be used for acute treatment periods up to two or three weeks • Adequate evidence of effectiveness for more prolonged use has not been established • Not recommended in pediatric patients less than 16 years of age •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carisoprodol is a centrally acting skeletal muscle relaxant that does not act directly on skeletal muscle but acts directly on the central nervous system (CNS). This drug relieves the painful effects of muscle spasm. A metabolite of carisoprodol, meprobamate, possesses both anxiolytic and sedative properties. Clinical studies have shown that this drug causes impairment of psychomotor performance in neuropsychological tests. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of carisoprodol in relieving discomfort associated with acute painful musculoskeletal conditions has not been confirmed. In studies using animal models, the muscle relaxation that is induced by carisoprodol is associated with a change in the interneuronal activity of the spinal cord and of the descending reticular formation, located in the brain. The abuse potential of this drug is attributed to its ability to alter GABAA function. This drug has been shown to modulate a variety of GABAA receptor subunits. GABAA receptor modulation can lead to anxiolysis due to inhibitory effects on neurotransmission. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absolute bioavailability of carisoprodol has not yet been established. The mean time to peak plasma concentrations (Tmax) of this drug was about 1.5-2 hours in clinical studies. Co-administration of a fatty meal with carisoprodol (350 mg tablet) had no impact on carisoprodol pharmacokinetics. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 0.93 to 1.3 L/kg, according to 4 different clinical studies. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 60%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The main pathway of carisoprodol is liver metabolism is by the cytochrome enzyme CYP2C19 to form meprobamate. This enzyme exhibits genetic polymorphism, which may affect the metabolism of this drug. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Carisoprodol is eliminated by the kidneys as well as other routes. The half-life of meprobamate is approximately 10 hours. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life is approximately 2 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Following an oral dose of carisoprodol, the oral clearance (Cl/F) was 39.52 ± 16.83 L/hour. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): LD50 values The LD50 values of carisoprodol for rats are 450 mg/kg for intravenous (IV) and intraperitoneal injection, and 1,320 mg/kg for gavage dosing. In mice, the LD50 values are 165 mg/kg for intravenous injection, 980 mg/kg for intraperitoneal injection, and 2,340 mg/kg for gavage dosing. The LD50 value for rabbits given carisoprodol by intravenous injection is 124 mg/kg. Overdose An overdose of carisoprodol leads to CNS depression, and in severe cases, induction of a coma. Shock, depression of respiratory function, seizures and death have also been reported in rare cases. Several symptoms may be associated with carisoprodol overdose, such as horizontal and vertical nystagmus, blurred vision, mydriasis, mild tachycardia and hypotension, respiratory depression, euphoria, CNS stimulation, muscular incoordination, and/or rigidity, confusion, headache, hallucinations, and dystonic reactions. Alcohol or other CNS depressants or psychotropic agents can exert additive effects on carisoprodol even when one of the agents has been ingested at the normal, therapeutic dose. Fatal accidental and non-accidental overdoses have both been reported with carisoprodol ingestion alone or ingestion of carisoprodol in combination with alcohol or psychotropic drugs. A note on dependence and withdrawal In the postmarketing reports after carisoprodol use, cases of dependence, withdrawal, and abuse have been reported with long-term use. The majority of dependence and withdrawal cases, as well as abuse, have occurred in patients with a history of addiction or who have used this drug in combination with other drugs having abuse potential. However, multiple post-marketing adverse event reports have been made of carisodopril-associated abuse when used without other drugs possessing abuse potential. Withdrawal symptoms have been observed and reported following sudden abrupt cessation after long-term carisodoprol use. To reduce the chance of carisodopril dependence, withdrawal, or abuse, carisodopril should be used with caution in addiction-prone patients and in patients taking other CNS depressants including alcohol. This drug should not be taken for longer than 2 to 3 weeks for symptomatic relief of acute musculoskeletal discomfort. Use in pregnancy This drug has been classified as Pregnancy Category C. There are no clinical trial data on the use of carisoprodol during human pregnancy. Animal studies show that carisoprodol crosses the placenta and leads to adverse effects on fetal growth and postnatal survival. In postmarketing reports, the main metabolite, meprobamate, has not demonstrated a consistent association between maternal use and an increased risk for specific congenital malformations. Use in nursing Limited data in humans demonstrate that this is found excreted in breast milk and may reach concentrations in breast milk of 2-4 times the maternal plasma concentrations. It is therefore advisable to exercise caution when this drug is used during breastfeeding. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Soma, Vanadom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carisoprodol Carisoprodolo Carisoprodolum Isobamate Isomeprobamate Isopropyl meprobamate Isopropylmeprobamate •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carisoprodol is a centrally acting muscle relaxant used to relieve the discomfort associated with various musculoskeletal conditions. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Adalimumab and Carmustine interact?

•Drug A: Adalimumab •Drug B: Carmustine •Severity: MODERATE •Description: The metabolism of Carmustine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carmustine is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carmustine causes cross-links in DNA and RNA, leading to the inhibition of DNA synthesis, RNA production and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamoylates) glutathione reductase. This leads to cell death. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): 5 to 28% bioavailability •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 80% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic and rapid with active metabolites. Metabolites may persist in the plasma for several days. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 15-30 minutes •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 s in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, nausea. Toxic effects include pulmonary fibrosis (20-0%) and bone marrow toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bicnu, Gliadel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): BCNU bis-chloroethylnitrosourea Bischloroethyl nitrosourea Carmustina Carmustine Carmustinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carmustine is an alkylating agent used in the treatment of various malignancies, including brain tumours and multiple myeloma, among others.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Carmustine interact? Information: •Drug A: Adalimumab •Drug B: Carmustine •Severity: MODERATE •Description: The metabolism of Carmustine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of brain tumors, multiple myeloma, Hodgkin's disease and Non-Hodgkin's lymphomas. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carmustine is one of the nitrosoureas indicated as palliative therapy as a single agent or in established combination therapy with other approved chemotherapeutic agents in treatment of brain tumors, multiple myeloma, Hodgkin's disease, and non-Hodgkin's lymphomas. Although it is generally agreed that carmustine alkylates DNA and RNA, it is not cross resistant with other alkylators. As with other nitrosoureas, it may also inhibit several key enzymatic processes by carbamoylation of amino acids in proteins. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carmustine causes cross-links in DNA and RNA, leading to the inhibition of DNA synthesis, RNA production and RNA translation (protein synthesis). Carmustine also binds to and modifies (carbamoylates) glutathione reductase. This leads to cell death. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): 5 to 28% bioavailability •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 80% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic and rapid with active metabolites. Metabolites may persist in the plasma for several days. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as respiratory CO2. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 15-30 minutes •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 s in rat and mouse are 20 mg/kg and 45 mg/kg, respectively. Side effects include leukopenia, thrombocytopenia, nausea. Toxic effects include pulmonary fibrosis (20-0%) and bone marrow toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bicnu, Gliadel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): BCNU bis-chloroethylnitrosourea Bischloroethyl nitrosourea Carmustina Carmustine Carmustinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carmustine is an alkylating agent used in the treatment of various malignancies, including brain tumours and multiple myeloma, among others. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Carvedilol interact?

•Drug A: Adalimumab •Drug B: Carvedilol •Severity: MODERATE •Description: The metabolism of Carvedilol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carvedilol inhibits exercise induce tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Carvedilol has a bioavailability of 25-35%. Carvedilol has a T max of 1 to 2 hours. Taking carvedilol with a meal increases T max without increasing AUC. Carvedilol doses of 50mg lead to a C max of 122-262µg/L and an AUC of 717-1600µg/L*h. Carvedilol doses of 25mg lead to a C max of 24-151µg/L and an AUC of 272-947µg/L*h. Carvedilol doses of 12.5mg lead to a C max of 58-69µg/L and an AUC of 208-225µg/L*h. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Carvedilol has a volume of distribution of 1.5-2L/kg or 115L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The plasma clearance of carvedilol has been reported as 0.52L/kg or 500-700mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Coreg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carvedilol Carvédilol Carvedilolum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carvedilol is a non selective beta-adrenergic antagonist used to treat mild to severe chronic heart failure, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Carvedilol interact? Information: •Drug A: Adalimumab •Drug B: Carvedilol •Severity: MODERATE •Description: The metabolism of Carvedilol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Carvedilol is indicated to treat mild to severe heart failure, left ventricular dysfunction after myocardial infarction with ventricular ejection fraction ≤40%, or hypertension. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Carvedilol reduces tachycardia through beta adrenergic antagonism and lowers blood pressure through alpha-1 adrenergic antagonism. It has a long duration of action as it is generally taken once daily and has a broad therapeutic index as patients generally take 10-80mg daily. Patients taking carvedilol should not abruptly stop taking this medication as this may exacerbate coronary artery disease. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Carvedilol inhibits exercise induce tachycardia through its inhibition of beta adrenoceptors. Carvedilol's action on alpha-1 adrenergic receptors relaxes smooth muscle in vasculature, leading to reduced peripheral vascular resistance and an overall reduction in blood pressure. At higher doses, calcium channel blocking and antioxidant activity can also be seen. The antioxidant activity of carvedilol prevents oxidation of low density lipoprotein and its uptake into coronary circulation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Carvedilol has a bioavailability of 25-35%. Carvedilol has a T max of 1 to 2 hours. Taking carvedilol with a meal increases T max without increasing AUC. Carvedilol doses of 50mg lead to a C max of 122-262µg/L and an AUC of 717-1600µg/L*h. Carvedilol doses of 25mg lead to a C max of 24-151µg/L and an AUC of 272-947µg/L*h. Carvedilol doses of 12.5mg lead to a C max of 58-69µg/L and an AUC of 208-225µg/L*h. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Carvedilol has a volume of distribution of 1.5-2L/kg or 115L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Carvedilol is 98% protein bound in plasma. 95% of carvedilol is bound to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Carvedilol can be hydroxlated at the 1 position by CYP2D6, CYP1A2, or CYP1A1 to form 1-hydroxypheylcarvedilol; at the 4 position by CYP2D6, CYP2E1, CYP2C9, or CYP3A4 to form 4'-hydroxyphenylcarvedilol; at the 5 position by CYP2D6, CYP2C9, or CYP3A4 to form 5'-hydroxyphenylcarvedilol; and at the 8 position by CYP1A2, CYP3A4, and CYP1A1 to form 8-hydroxycarbazolylcarvedilol. Carvedilol can also be demethylated by CYP2C9, CYP2D6, CYP1A2, or CYP2E1 to form O-desmethylcarvedilol. Carvedilol and its metabolites may undergo further sulfate conjugation or glucuronidation before elimination. Carvedilol can be O-glucuronidated by UGT1A1, UGT2B4, and UGT2B7 to form carvedilol glucuronide. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 16% of carvedilol is excreted in the urine with <2% excreted as unmetabolized drug. Carvedilol is primarily excreted in the bile and feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half life of carvedilol is between 7-10 hours, though significantly shorter half lives have also been reported. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The plasma clearance of carvedilol has been reported as 0.52L/kg or 500-700mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Patients experiencing an overdose may present with hypotension, bradycardia, cardiac insufficiency, cardiogenic shock, and cardiac arrest. Patients should remain in a supine position and may be given atropine for bradycardia and glucagon followed by sympathomimetics to support cardiovascular function. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Coreg •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Carvedilol Carvédilol Carvedilolum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Carvedilol is a non selective beta-adrenergic antagonist used to treat mild to severe chronic heart failure, hypertension, and left ventricular dysfunction following myocardial infarction in clinically stable patients. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Casirivimab interact?

•Drug A: Adalimumab •Drug B: Casirivimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Casirivimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): According to the Emergency Use Authorization (EUA) by the FDA and EMA, indevimab is used only with casirivimab to prevent COVID-19 and treat mild to moderate COVID-19 from laboratory-confirmed SARS-CoV-2 infection in patients aged 12 years of age and older who weigh at least 40 kg. Treatment is reserved for patients who are at high risk for progressing to require hospitalization or severe COVID-19. This combination may only be administered by intravenous infusion in healthcare settings with immediate access to treatment for infusion reactions and anaphylaxis, and the ability to activate the emergency medical system (EMS), as required. Limitations of use Imdevimab and casirivimab are not for use in patients currently hospitalized due to COVID-19, patients requiring oxygen therapy due to COVID-19, patients requiring increases in baseline oxygen flow rate from COVID-19, or patients on oxygen therapy for non-COVID-19 related morbidity. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Casirivimab and imdevimab work to neutralize the spike protein of SARS-CoV-2. In a clinical trial, casirivimab and imdevimab, when given together, reduced COVID-19-related hospitalization or emergency room visits in patients diagnosed with COVID-19 who were at high risk for disease progression within 28 days after treatment. No benefit has been shown in patients already hospitalized due to COVID-19 receiving this combination. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Casirivimab is a recombinant human IgG1 monoclonal antibody targeting the receptor binding domain of the spike protein of SARS-CoV-2; a protein playing an important role in viral attachment, fusion, and entry into the cell. Together with imdevimab, casirivimab neutralizes the spike protein of SARS-CoV-2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is limited information on overdose. Up to 4000 mg, which is approximately seven times the recommended dose of the drug, was administered in clinical trials. There is no known specific antidote for casirivimab overdose so treatment of overdose should involve general supportive measures. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Casirivimab is part of an investigational recombinant monoclonal antibody cocktail used to treat mild to moderate COVID-19.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Casirivimab interact? Information: •Drug A: Adalimumab •Drug B: Casirivimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Casirivimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): According to the Emergency Use Authorization (EUA) by the FDA and EMA, indevimab is used only with casirivimab to prevent COVID-19 and treat mild to moderate COVID-19 from laboratory-confirmed SARS-CoV-2 infection in patients aged 12 years of age and older who weigh at least 40 kg. Treatment is reserved for patients who are at high risk for progressing to require hospitalization or severe COVID-19. This combination may only be administered by intravenous infusion in healthcare settings with immediate access to treatment for infusion reactions and anaphylaxis, and the ability to activate the emergency medical system (EMS), as required. Limitations of use Imdevimab and casirivimab are not for use in patients currently hospitalized due to COVID-19, patients requiring oxygen therapy due to COVID-19, patients requiring increases in baseline oxygen flow rate from COVID-19, or patients on oxygen therapy for non-COVID-19 related morbidity. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Casirivimab and imdevimab work to neutralize the spike protein of SARS-CoV-2. In a clinical trial, casirivimab and imdevimab, when given together, reduced COVID-19-related hospitalization or emergency room visits in patients diagnosed with COVID-19 who were at high risk for disease progression within 28 days after treatment. No benefit has been shown in patients already hospitalized due to COVID-19 receiving this combination. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Casirivimab is a recombinant human IgG1 monoclonal antibody targeting the receptor binding domain of the spike protein of SARS-CoV-2; a protein playing an important role in viral attachment, fusion, and entry into the cell. Together with imdevimab, casirivimab neutralizes the spike protein of SARS-CoV-2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is limited information on overdose. Up to 4000 mg, which is approximately seven times the recommended dose of the drug, was administered in clinical trials. There is no known specific antidote for casirivimab overdose so treatment of overdose should involve general supportive measures. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Casirivimab is part of an investigational recombinant monoclonal antibody cocktail used to treat mild to moderate COVID-19. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Celecoxib interact?

•Drug A: Adalimumab •Drug B: Celecoxib •Severity: MODERATE •Description: The metabolism of Celecoxib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Celecoxib is indicated for symptomatic treatment of adult osteoarthritis (OA) and adult rheumatoid arthritis (RA). Celecoxib is not a substitute for aspirin for cardiovascular event prophylaxis. It may be also be used to treat acute pain from various sources, juvenile rheumatoid arthritis in children over 2, ankylosing spondylitis, and primary dysmenorrhea. Celecoxib, in combination with tramadol, is indicated for the management of acute pain in adults severe enough to require an opioid analgesic and in whom alternative treatments are inadequate. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Celecoxib inhibits cyclooxygenase 2 (COX-2) enzyme, reducing pain and inflammation. It is important to note that though the risk of bleeding with celecoxib is lower than with certain other NSAIDS, it exists nonetheless and caution must be observed when it is administered to those with a high risk of gastrointestinal bleeding. A note on the risk of cardiovascular events Significant concerns regarding the safety of COX-2 selective NSAIDs emerged in the early 2000s. Rofecoxib, another member of the COX-2 inhibitor drug class, also known as Vioxx, was withdrawn from the market due to prothrombotic cardiovascular risks. Following an FDA Advisory Committee meeting in 2005, in which data from large clinical outcome trials were evaluated, the FDA concluded that the risk for cardiovascular thrombotic events for both COX-2 selective NSAIDs and nonselective NSAIDs was evident. It was determined that the benefits of celecoxib treatment, however, outweighed the risks. Postmarketing cardiovascular outcomes trial (PRECISION) revealed that the lowest possible dose of celecoxib was similar in cardiovascular safety to moderate strength doses of both naproxen and ibuprofen. Patients who had previous cardiovascular events including acute MI, coronary revascularization, or coronary stent insertion were not evaluated in the trial. It is not advisable to administer NSAIDS to these groups of patients. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), celecoxib is a selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme. COX-2 is expressed heavily in inflamed tissues where it is induced by inflammatory mediators. The inhibition of this enzyme reduces the synthesis of metabolites that include prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 (PGF2). Resultant inhibition of these mediators leads to the alleviation of pain and inflammation. By inhibiting prostaglandin synthesis, non-steroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage, ulceration and ulcer complication throughout the gastrointestinal tract. Celecoxib poses less of an ulceration risk than other NSAIDS, owing to its decreased effect on gastric mucosal prostaglandin synthesis when compared to placebo. Celecoxib exerts anticancer effects by binding to the cadherin-11 (CDH11)protein, which is thought to be involved in the progression of tumors, and inhibiting the 3-phosphoinositide-dependent kinase-1 (PDK-1) signaling mechanism. In addition, celecoxib has been found to inhibit carbonic anhydrase enzymes 2 and 3, further enhancing its anticancer effects. As mentioned in the pharmacodynamics section of this drug entry, celecoxib may cause an increased risk of thrombotic events. The risk of thrombosis resulting from COX-2 inhibition is caused by the vasoconstricting actions of thromboxane A2, leading to enhanced platelet aggregation, which is uncontrolled when the actions of prostacyclin, a platelet aggregation inhibitor, are suppressed through the inhibition of COX-2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Celecoxib is absorbed rapidly in the gastrointestinal tract. When a single oral dose of 200 mg was given to healthy research subjects, the peak plasma levels of celecoxib occurred within 3 hours. The Cmax is 705 ng/mL. When multiple doses are given, steady-state concentrations are reached on or before day 5. When taken with a high-fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. The AUC of celecoxib has been shown to be significantly lower in patients with chronic renal impairment. A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC (area under the curve) of celecoxib in black patients compared to Caucasians for unknown reasons. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of celecoxib at steady state (Vss/F) is about 429 L, which suggests wide distribution into various tissues. Celecoxib is not preferentially bound to red blood cells. Another resource reports a volume of distribution of 455 ± 166L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of celecoxib is 97%, and it is primarily bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): A large part of celecoxib metabolism is mediated by cytochrome P450 2C9 in the liver with some contribution from CYP3A4 and CYP2C8 and possible contributions from CYP2D6. It is metabolized by biotransformation to carboxylic acid and glucuronide metabolites. Three metabolites, a primary alcohol, a carboxylic acid, and a glucuronide conjugate, have been found in human plasma after celecoxib administration. These are considered inactive metabolites in regards to COX enzyme inhibition. Patients who are known or suspected to have decreased cytochrome P450 2C9 activity or function, based on their previous history, should be administered celecoxib with caution as they may have abnormally high serum concentrations resulting from decreased metabolism celecoxib. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Celecoxib is primarily eliminated by hepatic metabolism with small amounts (<3%) of the unchanged drug found in both the urine and feces. About 57% of an oral dose of celecoxib is excreted in the feces and 27% is found to be excreted into the urine in the form of metabolites. The main metabolite in urine and feces is identified as the carboxylic acid metabolite (73%). The amount of glucuronide in the urine is reported to be low. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The effective half-life of celecoxib is approximately 11 hours when a single 200 mg dose is given to healthy subjects. The terminal half-life of celecoxib varies because of its low solubility, which prolongs absorption. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Apparent clearance (CL/F), single oral 200 mg dose, healthy subjects = 27.7 L/hr. Clearance may be decreased by about 47% in patients with chronic renal insufficiency, according to a pharmacokinetic study. Studies have not been performed in patients with severe renal impairment. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral TDLo in humans 5.71 mg/kg. It is not advisable to administer celecoxib in patients with renal impairment or advanced hepatic impairment, as this may lead to increased serum concentrations, causing toxicity. Symptoms of overdose may include breathing difficulties, coma, drowsiness, gastrointestinal bleeding, high blood pressure, kidney failure, nausea, sluggishness, stomach pain, and vomiting. Because serious gastrointestinal tract ulceration and bleeding can occur without preceding symptoms, patients should be monitored for signs/symptoms of gastrointestinal bleeding. Symptomatic and supportive measures should be taken in a celecoxib overdose. The induction of emesis or administration of active charcoal should take place if the patient is seen within 4 hours of celecoxib ingestion. Diuresis, urinary alkalinization, hemodialysis, or hemoperfusion may not be useful in a celecoxib overdose due to its high level of protein binding. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Celebrex, Elyxyb, Seglentis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celecoxib Célécoxib Celecoxibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Celecoxib is an NSAID used to treat osteoarthritis, rheumatoid arthritis, acute pain, menstrual symptoms, and to reduce polyps is familial adenomatous polyposis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Celecoxib interact? Information: •Drug A: Adalimumab •Drug B: Celecoxib •Severity: MODERATE •Description: The metabolism of Celecoxib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Celecoxib is indicated for symptomatic treatment of adult osteoarthritis (OA) and adult rheumatoid arthritis (RA). Celecoxib is not a substitute for aspirin for cardiovascular event prophylaxis. It may be also be used to treat acute pain from various sources, juvenile rheumatoid arthritis in children over 2, ankylosing spondylitis, and primary dysmenorrhea. Celecoxib, in combination with tramadol, is indicated for the management of acute pain in adults severe enough to require an opioid analgesic and in whom alternative treatments are inadequate. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Celecoxib inhibits cyclooxygenase 2 (COX-2) enzyme, reducing pain and inflammation. It is important to note that though the risk of bleeding with celecoxib is lower than with certain other NSAIDS, it exists nonetheless and caution must be observed when it is administered to those with a high risk of gastrointestinal bleeding. A note on the risk of cardiovascular events Significant concerns regarding the safety of COX-2 selective NSAIDs emerged in the early 2000s. Rofecoxib, another member of the COX-2 inhibitor drug class, also known as Vioxx, was withdrawn from the market due to prothrombotic cardiovascular risks. Following an FDA Advisory Committee meeting in 2005, in which data from large clinical outcome trials were evaluated, the FDA concluded that the risk for cardiovascular thrombotic events for both COX-2 selective NSAIDs and nonselective NSAIDs was evident. It was determined that the benefits of celecoxib treatment, however, outweighed the risks. Postmarketing cardiovascular outcomes trial (PRECISION) revealed that the lowest possible dose of celecoxib was similar in cardiovascular safety to moderate strength doses of both naproxen and ibuprofen. Patients who had previous cardiovascular events including acute MI, coronary revascularization, or coronary stent insertion were not evaluated in the trial. It is not advisable to administer NSAIDS to these groups of patients. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), celecoxib is a selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme. COX-2 is expressed heavily in inflamed tissues where it is induced by inflammatory mediators. The inhibition of this enzyme reduces the synthesis of metabolites that include prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 (PGF2). Resultant inhibition of these mediators leads to the alleviation of pain and inflammation. By inhibiting prostaglandin synthesis, non-steroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage, ulceration and ulcer complication throughout the gastrointestinal tract. Celecoxib poses less of an ulceration risk than other NSAIDS, owing to its decreased effect on gastric mucosal prostaglandin synthesis when compared to placebo. Celecoxib exerts anticancer effects by binding to the cadherin-11 (CDH11)protein, which is thought to be involved in the progression of tumors, and inhibiting the 3-phosphoinositide-dependent kinase-1 (PDK-1) signaling mechanism. In addition, celecoxib has been found to inhibit carbonic anhydrase enzymes 2 and 3, further enhancing its anticancer effects. As mentioned in the pharmacodynamics section of this drug entry, celecoxib may cause an increased risk of thrombotic events. The risk of thrombosis resulting from COX-2 inhibition is caused by the vasoconstricting actions of thromboxane A2, leading to enhanced platelet aggregation, which is uncontrolled when the actions of prostacyclin, a platelet aggregation inhibitor, are suppressed through the inhibition of COX-2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Celecoxib is absorbed rapidly in the gastrointestinal tract. When a single oral dose of 200 mg was given to healthy research subjects, the peak plasma levels of celecoxib occurred within 3 hours. The Cmax is 705 ng/mL. When multiple doses are given, steady-state concentrations are reached on or before day 5. When taken with a high-fat meal, peak plasma levels are delayed for about 1 to 2 hours with an increase in total absorption (AUC) of 10% to 20%. The AUC of celecoxib has been shown to be significantly lower in patients with chronic renal impairment. A meta-analysis of pharmacokinetic studies has suggested an approximately 40% higher AUC (area under the curve) of celecoxib in black patients compared to Caucasians for unknown reasons. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of celecoxib at steady state (Vss/F) is about 429 L, which suggests wide distribution into various tissues. Celecoxib is not preferentially bound to red blood cells. Another resource reports a volume of distribution of 455 ± 166L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of celecoxib is 97%, and it is primarily bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): A large part of celecoxib metabolism is mediated by cytochrome P450 2C9 in the liver with some contribution from CYP3A4 and CYP2C8 and possible contributions from CYP2D6. It is metabolized by biotransformation to carboxylic acid and glucuronide metabolites. Three metabolites, a primary alcohol, a carboxylic acid, and a glucuronide conjugate, have been found in human plasma after celecoxib administration. These are considered inactive metabolites in regards to COX enzyme inhibition. Patients who are known or suspected to have decreased cytochrome P450 2C9 activity or function, based on their previous history, should be administered celecoxib with caution as they may have abnormally high serum concentrations resulting from decreased metabolism celecoxib. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Celecoxib is primarily eliminated by hepatic metabolism with small amounts (<3%) of the unchanged drug found in both the urine and feces. About 57% of an oral dose of celecoxib is excreted in the feces and 27% is found to be excreted into the urine in the form of metabolites. The main metabolite in urine and feces is identified as the carboxylic acid metabolite (73%). The amount of glucuronide in the urine is reported to be low. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The effective half-life of celecoxib is approximately 11 hours when a single 200 mg dose is given to healthy subjects. The terminal half-life of celecoxib varies because of its low solubility, which prolongs absorption. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Apparent clearance (CL/F), single oral 200 mg dose, healthy subjects = 27.7 L/hr. Clearance may be decreased by about 47% in patients with chronic renal insufficiency, according to a pharmacokinetic study. Studies have not been performed in patients with severe renal impairment. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral TDLo in humans 5.71 mg/kg. It is not advisable to administer celecoxib in patients with renal impairment or advanced hepatic impairment, as this may lead to increased serum concentrations, causing toxicity. Symptoms of overdose may include breathing difficulties, coma, drowsiness, gastrointestinal bleeding, high blood pressure, kidney failure, nausea, sluggishness, stomach pain, and vomiting. Because serious gastrointestinal tract ulceration and bleeding can occur without preceding symptoms, patients should be monitored for signs/symptoms of gastrointestinal bleeding. Symptomatic and supportive measures should be taken in a celecoxib overdose. The induction of emesis or administration of active charcoal should take place if the patient is seen within 4 hours of celecoxib ingestion. Diuresis, urinary alkalinization, hemodialysis, or hemoperfusion may not be useful in a celecoxib overdose due to its high level of protein binding. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Celebrex, Elyxyb, Seglentis •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celecoxib Célécoxib Celecoxibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Celecoxib is an NSAID used to treat osteoarthritis, rheumatoid arthritis, acute pain, menstrual symptoms, and to reduce polyps is familial adenomatous polyposis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Celiprolol interact?

•Drug A: Adalimumab •Drug B: Celiprolol •Severity: MODERATE •Description: The metabolism of Celiprolol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 25-30%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celiprolol Celiprololum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Celiprolol is a beta-blocker for the management of hypertension and angina pectoris.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Celiprolol interact? Information: •Drug A: Adalimumab •Drug B: Celiprolol •Severity: MODERATE •Description: The metabolism of Celiprolol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Celiprolol is indicated for the management of mild to moderate hypertension and effort-induced angina pectoris. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Celiprolol is a vasoactive beta-1 selective adrenoceptor antagonist with partial beta-2 agonist activity. The beta-2 agonist activity is thought to account for its mild vasodilating properties. It lowers blood pressure in hypertensive patients at rest and on exercise. The effects on heart rate and cardiac output are dependent on the pre-existing background level of sympathetic tone. Under conditions of stress such as exercise, celiprolol attenuates chronotropic and inotropic responses to sympathetic stimulation. However, at rest minimal impairment of cardiac function is seen. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Absorption of an oral dose is rapid and consistent but incomplete (55% for 200 mg dose and 74% for 400 mg dose) from the gastrointestinal tract. The bioavailability of celiprolol has been shown to be markedly affected by food and one should avoid administration of celiprolol with food. Coadministration of chlorthalidone, hydrochlorothiazide and theophylline also reduces the bioavailability of celiprolol. Following oral dosing, maximal blood concentrations are reached between 2 and 3 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The distribution volume is 4.5L/kg. Celiprolol is hydrophilic and does not cross the blood-brain barrier. The binding to plasma proteins is about 25-30%. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 25-30%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): A 14C labelled dose was completely recovered within 48 hours. The first-pass effect in the liver is insignificant. Celiprolol is metabolized to a minor extent (1-3%). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Cleared by both renal and non-renal excretory pathways. Celiprolol is not recommended for patients with creatinine clearance less than 15 mL per minute. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No data are available regarding celiprolol overdose in humans. The most common symptoms to be expected following overdosage with beta-adrenoceptor blocking agents are bradycardia, hypotension, bronchospasm and acute cardiac insufficiency. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Celiprolol Celiprololum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Celiprolol is a beta-blocker for the management of hypertension and angina pectoris. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cemiplimab interact?

•Drug A: Adalimumab •Drug B: Cemiplimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cemiplimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cemiplimab is indicated to treat: Locally advanced or metastatic cutaneous squamous cell carcinoma (mCSCC) in patients who are not candidates for curative surgery or curative radiation. Locally advanced basal cell carcinoma (laBCC) in previously treated patients with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. Metastatic basal cell carcinoma (mBCC) in patients who were previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. This indication is approved under accelerated approval based on tumour response rate and durability of response. Continued approval for mBCC may be contingent upon verification and description of clinical benefit. Locally advanced non-small cell lung cancer (NSCLC) in combination with platinum‐based chemotherapy for the first‐line treatment of adults with no EGFR, ALK or ROS1 aberrations, who are not candidates for surgical resection or definitive chemoradiation. It is also indicated to treat metastatic NSCLC in combination with platinum‐based chemotherapy as first-line treatment in adults. Locally advanced or metastatic NSCLC as monotherapy for the first-line treatment of adults whose tumours have high PD-L1 expression [Tumor Proportion Score (TPS) ≥ 50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations. Patients with locally advanced NSCLC must not be candidates for surgical resection or definitive chemoradiation. Recurrent or metastatic cervical cancer in adults with disease progression on or after platinum-based chemotherapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cemiplimab inhibits tumour growth via an immune-mediated mechanism. Cemiplimab works to promote T cell-mediated immune response against tumours by blocking programmed death-1 (PD-1), a negative regulator of T cells. Cemiplimab targets PD-1 with high affinity and potency. In syngeneic mouse tumour models, blocking PD-1 activity by cemiplimab resulted in decreased tumour growth. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): T cells mediate antitumour activity following activation by antigen receptor signalling and CD28 costimulatory signalling. T cell proliferation and activation are regulated by a number of T cell immune regulatory checkpoints, including programmed death-1 (PD-1). PD-1 is an inhibitory co-receptor that is predominantly expressed on the surface of T cells to block T cell activation. Its ligands, PD-L1 and PD-L2, bind to PD-1 to activate downstream signalling cascades that ultimately result in the inhibition of T cell function such as T cell proliferation, cytokine production, and cytotoxicity. PD-1 receptor signalling pathway serves to maintain tolerance and regulate any ineffective or harmful immune responses; however, PD-1 signalling can also attenuate immune responses in cases where such protection is needed, such as autoimmune disorders and malignancy. PD-L1 and PD-L2 are expressed on antigen-presenting cells (APCs) as well as on some types of tumour cells as part of an adaptive immune response by tumours. PD-1 is also upregulated in some cancers, impeding T cell-mediated antitumour activity. Cemiplimab is a human PD-1-blocking antibody that binds to PD-1 and blocks its interaction with its ligands. By disinhibiting PD-1 mediated suppression of T cell activity, cemiplimab works to potentiate T cell cytotoxicity against tumours. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In a pharmacokinetic study involving patients with various solid tumours, the pharmacokinetics of cemiplimab was linear and dose-proportional in the dose range of 1 mg/kg to 10 mg/kg cemiplimab administered intravenously every two weeks. When cemiplimab was administered at a dose of 350 mg every three weeks, the median steady-state concentrations (coefficient of variation, CV%) of cemiplimab ranged between 61 mg/L (45%) and 171 mg/L (28%). Steady-state exposure is achieved after four months of treatment. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution (coefficient of variation, CV%) of cemiplimab at steady-state is 5.3 L (26%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No information is available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As with other monoclonal antibodies, cemiplimab is expected to undergo nonspecific degradation into small peptides and individual amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No information is available. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life (CV%) at steady state is 20.3 days (29%). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Cemiplimab clearance (CV%) after the first dose is 0.29 L/day (33%) and decreases over time by 29%, resulting in a steady-state clearance (CL ss ) (CV%) of 0.2 L/day (40%). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is limited information regarding acute toxicity and overdose of cemiplimab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be initiated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Libtayo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cemiplimab is a programmed death receptor-1 blocking antibody used to treat cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Cemiplimab interact? Information: •Drug A: Adalimumab •Drug B: Cemiplimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cemiplimab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cemiplimab is indicated to treat: Locally advanced or metastatic cutaneous squamous cell carcinoma (mCSCC) in patients who are not candidates for curative surgery or curative radiation. Locally advanced basal cell carcinoma (laBCC) in previously treated patients with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. Metastatic basal cell carcinoma (mBCC) in patients who were previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate. This indication is approved under accelerated approval based on tumour response rate and durability of response. Continued approval for mBCC may be contingent upon verification and description of clinical benefit. Locally advanced non-small cell lung cancer (NSCLC) in combination with platinum‐based chemotherapy for the first‐line treatment of adults with no EGFR, ALK or ROS1 aberrations, who are not candidates for surgical resection or definitive chemoradiation. It is also indicated to treat metastatic NSCLC in combination with platinum‐based chemotherapy as first-line treatment in adults. Locally advanced or metastatic NSCLC as monotherapy for the first-line treatment of adults whose tumours have high PD-L1 expression [Tumor Proportion Score (TPS) ≥ 50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations. Patients with locally advanced NSCLC must not be candidates for surgical resection or definitive chemoradiation. Recurrent or metastatic cervical cancer in adults with disease progression on or after platinum-based chemotherapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cemiplimab inhibits tumour growth via an immune-mediated mechanism. Cemiplimab works to promote T cell-mediated immune response against tumours by blocking programmed death-1 (PD-1), a negative regulator of T cells. Cemiplimab targets PD-1 with high affinity and potency. In syngeneic mouse tumour models, blocking PD-1 activity by cemiplimab resulted in decreased tumour growth. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): T cells mediate antitumour activity following activation by antigen receptor signalling and CD28 costimulatory signalling. T cell proliferation and activation are regulated by a number of T cell immune regulatory checkpoints, including programmed death-1 (PD-1). PD-1 is an inhibitory co-receptor that is predominantly expressed on the surface of T cells to block T cell activation. Its ligands, PD-L1 and PD-L2, bind to PD-1 to activate downstream signalling cascades that ultimately result in the inhibition of T cell function such as T cell proliferation, cytokine production, and cytotoxicity. PD-1 receptor signalling pathway serves to maintain tolerance and regulate any ineffective or harmful immune responses; however, PD-1 signalling can also attenuate immune responses in cases where such protection is needed, such as autoimmune disorders and malignancy. PD-L1 and PD-L2 are expressed on antigen-presenting cells (APCs) as well as on some types of tumour cells as part of an adaptive immune response by tumours. PD-1 is also upregulated in some cancers, impeding T cell-mediated antitumour activity. Cemiplimab is a human PD-1-blocking antibody that binds to PD-1 and blocks its interaction with its ligands. By disinhibiting PD-1 mediated suppression of T cell activity, cemiplimab works to potentiate T cell cytotoxicity against tumours. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In a pharmacokinetic study involving patients with various solid tumours, the pharmacokinetics of cemiplimab was linear and dose-proportional in the dose range of 1 mg/kg to 10 mg/kg cemiplimab administered intravenously every two weeks. When cemiplimab was administered at a dose of 350 mg every three weeks, the median steady-state concentrations (coefficient of variation, CV%) of cemiplimab ranged between 61 mg/L (45%) and 171 mg/L (28%). Steady-state exposure is achieved after four months of treatment. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution (coefficient of variation, CV%) of cemiplimab at steady-state is 5.3 L (26%). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No information is available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As with other monoclonal antibodies, cemiplimab is expected to undergo nonspecific degradation into small peptides and individual amino acids. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No information is available. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life (CV%) at steady state is 20.3 days (29%). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Cemiplimab clearance (CV%) after the first dose is 0.29 L/day (33%) and decreases over time by 29%, resulting in a steady-state clearance (CL ss ) (CV%) of 0.2 L/day (40%). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is limited information regarding acute toxicity and overdose of cemiplimab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic treatment should be initiated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Libtayo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cemiplimab is a programmed death receptor-1 blocking antibody used to treat cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Cenobamate interact?

•Drug A: Adalimumab •Drug B: Cenobamate •Severity: MODERATE •Description: The metabolism of Cenobamate can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cenobamate is indicated for the treatment of partial onset seizures in adults. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The mechanism of cenobamate is unknown, however it modulates GABA A and inhibit voltage gated sodium channels. Cenobamate is given once daily and so it has a long duration of action. The therapeutic window is wide as doses of 750mg can be well tolerated. Patients should be counselled regarding the risk of DRESS syndrome, QT interval shortening, suicidal behavior, and neurological adverse effects. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cenobamate inhibits voltage gated sodium channels and is a positive GABA A modulator. However, the exact mechanism of action remains unknown. Inhibition of voltage gated sodium channels increases the threshold for generating action potentials and decreases the number of action potentials. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cenobamate is 88% orally bioavailable with a T max of 1-4 hours. A high fat meal does not significantly impact the pharmacokinetics of cenobamate. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of cenobamate is 40-50L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cenobamate is 60% protein bound in plasma, mainly serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Data regarding the metabolism of cenobamate is lacking, however it is mostly glucuronidated by UGT2B7 and UGT2B4 or oxidized by a number of cytochromes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cenobamate is 87.8% eliminated in the urine and 5.2% in the feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half life of cenobamate is 50-60h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The apparent oral clearance of cenobamate is 0.45-0.63L/h for a 100-400mg/day dose. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is limited information regarding the signs, symptoms, and treatment of a cenobamate overdose. Symptomatic and supportive treatment is recommended and there is limited data on the utility of dialysis to remove cenobamate from blood. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ontozry, XCopri, Xcopri 250 Mg Maintenance Pack, Xcopri Titration Pack - 12.5 Mg (14), 25 Mg (14) 28 Count •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cenobamate is a small molecule drug indicated to treat partial onset seizures in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cenobamate interact? Information: •Drug A: Adalimumab •Drug B: Cenobamate •Severity: MODERATE •Description: The metabolism of Cenobamate can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cenobamate is indicated for the treatment of partial onset seizures in adults. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The mechanism of cenobamate is unknown, however it modulates GABA A and inhibit voltage gated sodium channels. Cenobamate is given once daily and so it has a long duration of action. The therapeutic window is wide as doses of 750mg can be well tolerated. Patients should be counselled regarding the risk of DRESS syndrome, QT interval shortening, suicidal behavior, and neurological adverse effects. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cenobamate inhibits voltage gated sodium channels and is a positive GABA A modulator. However, the exact mechanism of action remains unknown. Inhibition of voltage gated sodium channels increases the threshold for generating action potentials and decreases the number of action potentials. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cenobamate is 88% orally bioavailable with a T max of 1-4 hours. A high fat meal does not significantly impact the pharmacokinetics of cenobamate. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of cenobamate is 40-50L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cenobamate is 60% protein bound in plasma, mainly serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Data regarding the metabolism of cenobamate is lacking, however it is mostly glucuronidated by UGT2B7 and UGT2B4 or oxidized by a number of cytochromes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cenobamate is 87.8% eliminated in the urine and 5.2% in the feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half life of cenobamate is 50-60h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The apparent oral clearance of cenobamate is 0.45-0.63L/h for a 100-400mg/day dose. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is limited information regarding the signs, symptoms, and treatment of a cenobamate overdose. Symptomatic and supportive treatment is recommended and there is limited data on the utility of dialysis to remove cenobamate from blood. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ontozry, XCopri, Xcopri 250 Mg Maintenance Pack, Xcopri Titration Pack - 12.5 Mg (14), 25 Mg (14) 28 Count •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cenobamate is a small molecule drug indicated to treat partial onset seizures in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cephalexin interact?

•Drug A: Adalimumab •Drug B: Cephalexin •Severity: MODERATE •Description: The metabolism of Cephalexin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cephalexin is indicated for the treatment of certain infections caused by susceptible bacteria. These infections include respiratory tract infections, otitis media, skin and skin structure infections, bone infections, and genitourinary tract infections. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cephalexin (also called Cefalexin) is a first generation cephalosporin antibiotic. It is one of the most widely prescribed antibiotics, often used for the treatment of superficial infections that result as complications of minor wounds or lacerations. It is effective against most gram-positive bacteria through its inihibition of the cross linking reaction between N-acetyl muramicacid and N-acetylglucosamine in the cell wall, leading to cell lysis. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cephalexin is a first generation cephalosporin antibiotic. Cephalosporins contain a beta lactam and dihydrothiazide. Unlike penicillins, cephalosprins are more resistant to the action of beta lactamase. Cephalexin inhibits bacterial cell wall synthesis, leading breakdown and eventualy cell death. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed from the upper gastrointestinal tract with nearly 100% oral bioavailability. Cephalexin is not absorbed in the stomach but is absorbed in the upper intestine. Patients taking 250mg of cephalexin reach a maximum plasma concentration of 7.7mcg/mL and patients taking 500mg reach 12.3mcg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 5.2-5.8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cephalexin is 10-15% bound to serum proteins including serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cephalexin is not metabolized in the body. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cephalexin is over 90% excreted in the urine after 6 hours by glomerular filtration and tubular secretion with a mean urinary recovery of 99.3%. Cephalexin is unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half life of cephalexin is 49.5 minutes in a fasted state and 76.5 minutes with food though these times were not significantly different in the study. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Clearance from one subject was 376mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include blood in the urine, diarrhea, nausea, upper abdominal pain, and vomiting. An overdose is generally managed through supportive treatment as diuresis, dialysis, hemodialysis, and charcoal hemoperfusion are not well studied in this case. The oral median lethal dose of cephalexin in rats is >5000 mg/kg. The oral LD50 in a monkey is >1g/kg and the lowest dose causing a toxic effect in humans is 14mg/kg. Cephalexin has not been shown to be harmful in pregnancy and is not associated with teratogeniticy. Cephalexin is present in breast milk, though infants may be exposed to <1% of the dose given to the mother. The effects of breast milk exposure to cephalexin have not been established and so caution must be exercised and the risk and benefit of cephalexin use in breastfeeding must be weighed. Cephalexin has not been studied for carcinogenicity or mutagenicity. Cephalexin has no affect on fertility in rats. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Keflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cefalexin Cefalexina Céfalexine Cefalexinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cephalexin is a first generation cephalosporin used to treat certain susceptible bacterial infections.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cephalexin interact? Information: •Drug A: Adalimumab •Drug B: Cephalexin •Severity: MODERATE •Description: The metabolism of Cephalexin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cephalexin is indicated for the treatment of certain infections caused by susceptible bacteria. These infections include respiratory tract infections, otitis media, skin and skin structure infections, bone infections, and genitourinary tract infections. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cephalexin (also called Cefalexin) is a first generation cephalosporin antibiotic. It is one of the most widely prescribed antibiotics, often used for the treatment of superficial infections that result as complications of minor wounds or lacerations. It is effective against most gram-positive bacteria through its inihibition of the cross linking reaction between N-acetyl muramicacid and N-acetylglucosamine in the cell wall, leading to cell lysis. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cephalexin is a first generation cephalosporin antibiotic. Cephalosporins contain a beta lactam and dihydrothiazide. Unlike penicillins, cephalosprins are more resistant to the action of beta lactamase. Cephalexin inhibits bacterial cell wall synthesis, leading breakdown and eventualy cell death. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed from the upper gastrointestinal tract with nearly 100% oral bioavailability. Cephalexin is not absorbed in the stomach but is absorbed in the upper intestine. Patients taking 250mg of cephalexin reach a maximum plasma concentration of 7.7mcg/mL and patients taking 500mg reach 12.3mcg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 5.2-5.8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cephalexin is 10-15% bound to serum proteins including serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cephalexin is not metabolized in the body. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cephalexin is over 90% excreted in the urine after 6 hours by glomerular filtration and tubular secretion with a mean urinary recovery of 99.3%. Cephalexin is unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half life of cephalexin is 49.5 minutes in a fasted state and 76.5 minutes with food though these times were not significantly different in the study. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Clearance from one subject was 376mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include blood in the urine, diarrhea, nausea, upper abdominal pain, and vomiting. An overdose is generally managed through supportive treatment as diuresis, dialysis, hemodialysis, and charcoal hemoperfusion are not well studied in this case. The oral median lethal dose of cephalexin in rats is >5000 mg/kg. The oral LD50 in a monkey is >1g/kg and the lowest dose causing a toxic effect in humans is 14mg/kg. Cephalexin has not been shown to be harmful in pregnancy and is not associated with teratogeniticy. Cephalexin is present in breast milk, though infants may be exposed to <1% of the dose given to the mother. The effects of breast milk exposure to cephalexin have not been established and so caution must be exercised and the risk and benefit of cephalexin use in breastfeeding must be weighed. Cephalexin has not been studied for carcinogenicity or mutagenicity. Cephalexin has no affect on fertility in rats. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Keflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cefalexin Cefalexina Céfalexine Cefalexinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cephalexin is a first generation cephalosporin used to treat certain susceptible bacterial infections. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates. The severity of the interaction is moderate.

Does Adalimumab and Ceritinib interact?

•Drug A: Adalimumab •Drug B: Ceritinib •Severity: MAJOR •Description: The metabolism of Ceritinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half life is 41 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zykadia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Céritinib Ceritinib Ceritinibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Ceritinib is an antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients with inadequate clinical response or intolerance to crizotinib.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Ceritinib interact? Information: •Drug A: Adalimumab •Drug B: Ceritinib •Severity: MAJOR •Description: The metabolism of Ceritinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Ceritinib is a kinase inhibitor indicated for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This indication is approved under accelerated approval based on tumor response rate and duration of response. An improvement in survival or disease-related symptoms has not been established. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Ceritinib inhibits Anaplastic lymphoma kinase (ALK) also known as ALK tyrosine kinase receptor or CD246 (cluster of differentiation 246), which is an enzyme that in humans is encoded by the ALK gene. About 4-5% of NSCLCs have a chromosomal rearrangement that generates a fusion gene between EML4 (echinoderm microtubule-associated protein-like 4) and ALK (anaplastic lymphoma kinase), which results in constitutive kinase activity that contributes to carcinogenesis and seems to drive the malignant phenotype. Ceritinib exerts its therapeutic effect by inhibiting autophosphorylation of ALK, ALK-mediated phosphorylation of the downstream signaling protein STAT3, and proliferation of ALK-dependent cancer cells. Ceritinib has been shown to inhibit in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice and rats. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration of ceritinib, peak concentrations were achieved after approximately 4 to 6 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution (Vd/F) is 4230 L following a single 750 mg dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ceritinib is 97% bound to human plasma proteins, independent of drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro studies demonstrated that CYP3A was the major enzyme involved in the metabolic clearance of ceritinib. Following oral administration of a single 750 mg radiolabeled ceritinib dose, ceritinib as the parent compound was the main circulating component (82%) in human plasma. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following oral administration of a single 750 mg radiolabeled ceritinib dose, 92.3% of the administered dose was recovered in the feces (with 68% as unchanged parent compound) while 1.3% of the administered dose was recovered in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half life is 41 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric mean apparent clearance (CL/F) of ceritinib was lower at steady-state (33.2 L/h) after 750 mg daily dosing than after a single 750 mg dose (88.5 L/h). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There is not currently any data on carcinogenicity, effect on human fertility, or on early embryonic development. However, based on its mechanism of action, ceritinib may cause fetal harm when administered to pregnant women and should therefore be administered with effective contraception during treatment. Diarrhea, nausea, vomiting, or abdominal pain occurred in 96% of 255 patients including severe cases in 14% of patients. Drug-induced hepatotoxicity also occurred in 27% of 255 patients, presenting as alanine aminotransferase (ALT) levels greater than 5 times the upper limit of normal (ULN). Severe, life-threatening, or fatal interstitial lung disease (ILD)/pneumonitis, hyperglycaemia, and bradycardia have also been reported. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zykadia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Céritinib Ceritinib Ceritinibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Ceritinib is an antineoplastic kinase inhibitor used to treat anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) in patients with inadequate clinical response or intolerance to crizotinib. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Certolizumab pegol interact?

•Drug A: Adalimumab •Drug B: Certolizumab pegol •Severity: MAJOR •Description: The risk or severity of infection can be increased when Adalimumab is combined with Certolizumab pegol. •Extended Description: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors like certolizumab pegol in patients is associated with the possibility of developing lymphoma and other malignancies, some incidences of which can be fatal . Subsequently, there is a concern that if certolizumab pegol is used concomitantly with other TNF-α inhibitors that their additive, combined adverse effects could increase the risk, incidence, and/or severity of lymphoma and other malignancies in patients . Use of Certolizumab Pegol with other can consequently increase the risk of infection with no additional benefit. The mode of action behind this interaction is likely linked to the immunosuppressive activity that is naturally associated with the mechanism of action of TNF-α inhibitors . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Certolizumab pegol has been approved for several different conditions listed below: Symptomatic management of Chron's disease patients and for the maintenance of clinical response in patients with moderate to severe disease with inadequate response to conventional therapy. Treatment of adult patients with moderate to severely active rheumatoid arthritis. Treatment of adult patients with active psoriatic arthritis. Treatment of adult patients with active ankylosing spondylitis. Treatment of adult patients with moderate-to-severe plaque psoriasis that are candidates for systemic therapy or phototherapy. Treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation. In Canada, certolizumab pegol is additionally approved in combination with methotrexate for the symptomatic treatment, including major clinical response, and for the reduction of joint damage in adult patients with moderately to severely active rheumatoid arthritis and psoriatic arthritis. Inflammation is a biological response against a potential threat. This response can be normal but in certain conditions, the immune system can attack the body's normal cells or tissues which causes an abnormal inflammation. TNF-alpha has been identified as a key regulator of the inflammatory response. The signaling cascades of this inflammatory mediator can produce a wide range of reactions including cell death, survival, differentiation, proliferation and migration. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): As part of the mechanism of action and nature of the drug, certolizumab does not induce apoptosis in cultured lymphocytes and monocytes. However, as a piece of the inhibition of inflammation, certolizumab pegol inhibits lipopolysaccharide-induced production of IL-1 beta and it induces nonapoptotic cell death via signaling transmembrane TNF-alpha. In vitro studies with certolizumab pegol in human tissue did not show any unexpected binding at 3 mcg/ml nor at 10 mcg/ml. Due to the drug class, certolizumab pegol is not expected to present adverse effects on the major vital systems. In phase III clinical trials in psoriatic arthritis patients, certolizumab pegol was reported to generate improvements in skin disease, joint involvement, dactylitis, enthesitis and general life quality. The clinical effect of certolizumab was paired to a comparable safety profile to other TNF-alpha inhibitors. The clinical effectiveness of certolizumab pegol was mainly studied in six randomized controlled trials that compared its effect versus placebo. In a comparative study, the efficacy for certolizumab pegol registered ranged from 30-65% while in placebo ranged from 4-25%. However, in other additional trials, certolizumab was proven to present a similar clinical efficacy to other disease-modifying antirheumatic drugs in patients with inadequate response to TNF inhibitors. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Certolizumab targets the activation of TNF-alpha with high affinity (KD 90 pM and IC90 0.004 mcg/ml) which inhibits the downstream inflammatory process. It acts by binding and neutralizing the soluble and membrane portions of TNF-alpha without inducing complement or antibody-dependent cytotoxicity due to the lack of the Fc region. The inhibition of TNF-alpha is achieved in a dose-dependent manner and it does not present activity against lymphotoxin alpha (TNF-beta). One additional feature od certolizumab pegol is that, due to the presence of the PEGylation, it is more significantly distributed into inflamed tissues when compared to other TNF-alpha inhibitors such as infliximab and adalimumab. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After subcutaneous administration, the peak plasma concentration is reached between 54 and 171 hours with a bioavailability of 80%. Certolizumab presents a linear pharmacokinetic profile with a peak plasma concentration of 43-49 mcg/ml. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Certolizumab pegol volume of distribution is reported to be in the range of 4-8 L. It is known to have a very good distribution in the joints when compared to other TNF-alpha inhibitors. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Monoclonal antibodies are usually not required to have protein binding studies. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The presence of PEG group in certolizumab pegol delays the metabolism and elimination of this drug. However, once under metabolism, the PEG group gets cleaved from the parent compound and the antibody section is thought to be internalized cells and rescued from metabolism by recycling. Later, it is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. On the other hand, the PEG section is processed normally by the action of the alcohol dehydrogenase to the formation of carboxylic acid. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As certolizumab is a monoclonal antibody, the elimination route is not widely studied. However, it is known that the elimination of the PEG moiety is dependent on the renal function which links it directly with a high portion of renal elimination. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The circulatory half-life of certolizumab is of 14 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance rate of certolizumab pegol ranged between 9-14 ml/h when administered intravenously. However, when administered subcutaneously, the clearance rate is estimated to range between 14-21 ml/h depending on the patient condition. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral ld50 observed in mice is determined to be of 300 mg/kg. To this date, there have not been reports of overdosage, however, in case of accidental overexposure close monitoring is recommended. Certolizumab pegol does not present mutagenic potential nor presents effects in fertility and reproductive performance. On the other hand, carcinogenicity studies have not been performed. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cimzia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Certolizumab pegol is a tumor necrosis factor (TNF) blocker used to treat a variety of autoimmune and autoinflammatory conditions like Crohn's disease, rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, and plaque psoriasis.

Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors like certolizumab pegol in patients is associated with the possibility of developing lymphoma and other malignancies, some incidences of which can be fatal . Subsequently, there is a concern that if certolizumab pegol is used concomitantly with other TNF-α inhibitors that their additive, combined adverse effects could increase the risk, incidence, and/or severity of lymphoma and other malignancies in patients . Use of Certolizumab Pegol with other can consequently increase the risk of infection with no additional benefit. The mode of action behind this interaction is likely linked to the immunosuppressive activity that is naturally associated with the mechanism of action of TNF-α inhibitors . The severity of the interaction is major.

Question: Does Adalimumab and Certolizumab pegol interact? Information: •Drug A: Adalimumab •Drug B: Certolizumab pegol •Severity: MAJOR •Description: The risk or severity of infection can be increased when Adalimumab is combined with Certolizumab pegol. •Extended Description: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors like certolizumab pegol in patients is associated with the possibility of developing lymphoma and other malignancies, some incidences of which can be fatal . Subsequently, there is a concern that if certolizumab pegol is used concomitantly with other TNF-α inhibitors that their additive, combined adverse effects could increase the risk, incidence, and/or severity of lymphoma and other malignancies in patients . Use of Certolizumab Pegol with other can consequently increase the risk of infection with no additional benefit. The mode of action behind this interaction is likely linked to the immunosuppressive activity that is naturally associated with the mechanism of action of TNF-α inhibitors . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Certolizumab pegol has been approved for several different conditions listed below: Symptomatic management of Chron's disease patients and for the maintenance of clinical response in patients with moderate to severe disease with inadequate response to conventional therapy. Treatment of adult patients with moderate to severely active rheumatoid arthritis. Treatment of adult patients with active psoriatic arthritis. Treatment of adult patients with active ankylosing spondylitis. Treatment of adult patients with moderate-to-severe plaque psoriasis that are candidates for systemic therapy or phototherapy. Treatment of adult patients with active non-radiographic axial spondyloarthritis with objective signs of inflammation. In Canada, certolizumab pegol is additionally approved in combination with methotrexate for the symptomatic treatment, including major clinical response, and for the reduction of joint damage in adult patients with moderately to severely active rheumatoid arthritis and psoriatic arthritis. Inflammation is a biological response against a potential threat. This response can be normal but in certain conditions, the immune system can attack the body's normal cells or tissues which causes an abnormal inflammation. TNF-alpha has been identified as a key regulator of the inflammatory response. The signaling cascades of this inflammatory mediator can produce a wide range of reactions including cell death, survival, differentiation, proliferation and migration. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): As part of the mechanism of action and nature of the drug, certolizumab does not induce apoptosis in cultured lymphocytes and monocytes. However, as a piece of the inhibition of inflammation, certolizumab pegol inhibits lipopolysaccharide-induced production of IL-1 beta and it induces nonapoptotic cell death via signaling transmembrane TNF-alpha. In vitro studies with certolizumab pegol in human tissue did not show any unexpected binding at 3 mcg/ml nor at 10 mcg/ml. Due to the drug class, certolizumab pegol is not expected to present adverse effects on the major vital systems. In phase III clinical trials in psoriatic arthritis patients, certolizumab pegol was reported to generate improvements in skin disease, joint involvement, dactylitis, enthesitis and general life quality. The clinical effect of certolizumab was paired to a comparable safety profile to other TNF-alpha inhibitors. The clinical effectiveness of certolizumab pegol was mainly studied in six randomized controlled trials that compared its effect versus placebo. In a comparative study, the efficacy for certolizumab pegol registered ranged from 30-65% while in placebo ranged from 4-25%. However, in other additional trials, certolizumab was proven to present a similar clinical efficacy to other disease-modifying antirheumatic drugs in patients with inadequate response to TNF inhibitors. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Certolizumab targets the activation of TNF-alpha with high affinity (KD 90 pM and IC90 0.004 mcg/ml) which inhibits the downstream inflammatory process. It acts by binding and neutralizing the soluble and membrane portions of TNF-alpha without inducing complement or antibody-dependent cytotoxicity due to the lack of the Fc region. The inhibition of TNF-alpha is achieved in a dose-dependent manner and it does not present activity against lymphotoxin alpha (TNF-beta). One additional feature od certolizumab pegol is that, due to the presence of the PEGylation, it is more significantly distributed into inflamed tissues when compared to other TNF-alpha inhibitors such as infliximab and adalimumab. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After subcutaneous administration, the peak plasma concentration is reached between 54 and 171 hours with a bioavailability of 80%. Certolizumab presents a linear pharmacokinetic profile with a peak plasma concentration of 43-49 mcg/ml. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Certolizumab pegol volume of distribution is reported to be in the range of 4-8 L. It is known to have a very good distribution in the joints when compared to other TNF-alpha inhibitors. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Monoclonal antibodies are usually not required to have protein binding studies. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The presence of PEG group in certolizumab pegol delays the metabolism and elimination of this drug. However, once under metabolism, the PEG group gets cleaved from the parent compound and the antibody section is thought to be internalized cells and rescued from metabolism by recycling. Later, it is degraded in the reticuloendothelial system to small peptides and amino acids which can be used for de-novo protein synthesis. On the other hand, the PEG section is processed normally by the action of the alcohol dehydrogenase to the formation of carboxylic acid. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As certolizumab is a monoclonal antibody, the elimination route is not widely studied. However, it is known that the elimination of the PEG moiety is dependent on the renal function which links it directly with a high portion of renal elimination. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The circulatory half-life of certolizumab is of 14 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance rate of certolizumab pegol ranged between 9-14 ml/h when administered intravenously. However, when administered subcutaneously, the clearance rate is estimated to range between 14-21 ml/h depending on the patient condition. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral ld50 observed in mice is determined to be of 300 mg/kg. To this date, there have not been reports of overdosage, however, in case of accidental overexposure close monitoring is recommended. Certolizumab pegol does not present mutagenic potential nor presents effects in fertility and reproductive performance. On the other hand, carcinogenicity studies have not been performed. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cimzia •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Certolizumab pegol is a tumor necrosis factor (TNF) blocker used to treat a variety of autoimmune and autoinflammatory conditions like Crohn's disease, rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, axial spondyloarthritis, and plaque psoriasis. Output: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors like certolizumab pegol in patients is associated with the possibility of developing lymphoma and other malignancies, some incidences of which can be fatal . Subsequently, there is a concern that if certolizumab pegol is used concomitantly with other TNF-α inhibitors that their additive, combined adverse effects could increase the risk, incidence, and/or severity of lymphoma and other malignancies in patients . Use of Certolizumab Pegol with other can consequently increase the risk of infection with no additional benefit. The mode of action behind this interaction is likely linked to the immunosuppressive activity that is naturally associated with the mechanism of action of TNF-α inhibitors . The severity of the interaction is major.

Does Adalimumab and Cetuximab interact?

•Drug A: Adalimumab •Drug B: Cetuximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Cetuximab is combined with Adalimumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cetuximab indicated for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy. It is indicated for treating a recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with fluorouracil. It is indicated for recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy. Cetuximab is also indicated for K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test in combination with FOLFIRI, a chemotherapy combination that includes leucovorin, fluorouracil, and irinotecan; in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or as monotherapy in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. Additionally, cetuximab is also indicated for metastatic colorectal cancer that is BRAF V600E mutation-positive (as determined by an FDA-approved test) in combination with encorafenib but only after prior therapy. Cetuximab is not indicated for the treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cetuximab is an anticancer agent that works by inhibiting the growth and survival of epidermal growth factor receptor (EGFR)-expressing tumour cells with high specificity and higher affinity than epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), which are natural ligands of EGFR. Cetuximab works by inhibiting the growth and survival of EGFR-positive tumours. In vitro, it promotes antibody-dependent cellular cytotoxicity (ADCC) against certain human tumour types. On the contrary, cetuximab does not exert its anti-tumour effects on human tumour xenografts lacking EGFR expression. Cetuximab potentiates the cytotoxic effects of chemotherapeutics and radiation therapy when used in combination. In human tumour xenograft models in mice, cetuximab and irinotecan synergistically inhibited the growth of orthotopic anaplastic thyroid carcinoma xenografts in vitro and in vivo. Cetuximab potentiated the in vitro anti-proliferative and pro-apoptotic effect of irinotecan and achieved 93% in vivo inhibition of tumour growth when combined with irinotecan, compared to 77% and 79% inhibition when cetuximab and irinotecan were used alone, respectively. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and a type I receptor tyrosine kinase expressed on both normal and malignant cells. It has been investigated as a therapeutic target for anticancer treatment, as it is often upregulated in cancer types, including head and neck, colon, and rectal cancers. When activated by its ligand, EGFR undergoes a conformational change and dimerization to form homodimers or heterodimers with another member of the ErbB family of receptors. Dimerization of EGFR activates the intracellular tyrosine kinase region of EGFR and promotes autophosphorylation, initiating a series of downstream signalling cascades, including cell differentiation, proliferation, migration, angiogenesis, and apoptosis. This EGFR signalling pathway is often dysregulated in cancer cells, leading to aberrant cell growth and enhanced cell survival. Cetuximab is a monoclonal antibody that binds specifically to the EGFR on both normal and tumour cells to competitively inhibit the binding of epidermal growth factor (EGF) and other ligands that are produced by normal and tumour tissue epithelial cells. Upon binding to domain III of EGFR - which is the binding site for its growth factor ligands - cetuximab prevents the receptor from adopting an extended conformation and thereby inhibits EGFR activation, as well as phosphorylation and activation of receptor-associated kinases (MAPK, PI3K/Akt, Jak/Stat). Inhibition of the EGFR signalling pathway ultimately leads to inhibition of cell cycle progression, cell survival pathways, and tumour cell motility and invasion. Cetuximab also induces cell apoptosis and decreases matrix metalloproteinase and vascular endothelial growth factor (VEGF) production. In vitro, cetuximab was shown to inhibit tumour angiogenesis. Binding of cetuximab to EGFR also results in internalization of the antibody-receptor complex, leading to an overall downregulation of EGFR expression. K-ras is a small G-protein downstream of EGFR that plays an important role in promoting the EGFR signalling cascade: in some malignant cells, K-ras can acquire activating mutations in exon 2 and thus be continuously active regardless of EGFR regulation. Since mutant Ras proteins can isolate the pathway from the effect of EGFR, K-Ras mutations can render EGFR inhibitors like cetuximab ineffective in exerting anti-tumour effects. Cetuximab is thus only limited in its use for K-Ras wild-type, EGFR-expressing cancers. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After administration of a 400 mg/m initial dose followed by a 250 mg/m weekly dose, the steady-state levels of cetuximab was reached by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 µg/mL to 235 µg/mL and 41 µg/mL to 85 µg/mL, respectively. T max is about 3 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of the distribution is about 2-3 L/m and is independent of dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Like other monoclonal antibodies, cetuximab is expected to undergo lysosomal degradation by the reticuloendothelial system and protein catabolism by a target‐mediated disposition pathway. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): There is limited information available. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): After administration of a 400 mg/m initial dose followed by a 250 mg/m weekly dose, the mean half-life for cetuximab was approximately 112 hours, with a range of 63 to 230 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, the estimated clearance rate was 0.103 L/h. At doses ranging from 200 to 400 mg/m, complete saturation of systemic clearance was observed. In a population pharmacokinetic study, female patients had a 25% lower intrinsic cetuximab clearance than male patients, although there was no evidence of the need for dose modification based on sex. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The intravenous LD 50 is > 300 mg/kg in mice and > 200 mg/kg in rats. There is limited information on the overdose from cetuximab. In clinical trials, cetuximab was associated with serious and fatal infusion reactions, cardiopulmonary arrest or sudden death, and serious dermatologic toxicities. Pulmonary toxicities, such as interstitial lung disease, interstitial pneumonitis with non-cardiogenic pulmonary edema, and exacerbation of pre-existing fibrotic lung disease have been reported. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Erbitux •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cetuximab is an endothelial growth factor receptor binding fragment used to treat colorectal cancer as well as squamous cell carcinoma of the head and neck.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Cetuximab interact? Information: •Drug A: Adalimumab •Drug B: Cetuximab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Cetuximab is combined with Adalimumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cetuximab indicated for the treatment of locally or regionally advanced squamous cell carcinoma of the head and neck in combination with radiation therapy. It is indicated for treating a recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck in combination with platinum-based therapy with fluorouracil. It is indicated for recurrent or metastatic squamous cell carcinoma of the head and neck progressing after platinum-based therapy. Cetuximab is also indicated for K-Ras wild-type, EGFR-expressing, metastatic colorectal cancer as determined by an FDA-approved test in combination with FOLFIRI, a chemotherapy combination that includes leucovorin, fluorouracil, and irinotecan; in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy; or as monotherapy in patients who have failed oxaliplatin- and irinotecan-based chemotherapy or who are intolerant to irinotecan. Additionally, cetuximab is also indicated for metastatic colorectal cancer that is BRAF V600E mutation-positive (as determined by an FDA-approved test) in combination with encorafenib but only after prior therapy. Cetuximab is not indicated for the treatment of Ras-mutant colorectal cancer or when the results of the Ras mutation tests are unknown. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cetuximab is an anticancer agent that works by inhibiting the growth and survival of epidermal growth factor receptor (EGFR)-expressing tumour cells with high specificity and higher affinity than epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-α), which are natural ligands of EGFR. Cetuximab works by inhibiting the growth and survival of EGFR-positive tumours. In vitro, it promotes antibody-dependent cellular cytotoxicity (ADCC) against certain human tumour types. On the contrary, cetuximab does not exert its anti-tumour effects on human tumour xenografts lacking EGFR expression. Cetuximab potentiates the cytotoxic effects of chemotherapeutics and radiation therapy when used in combination. In human tumour xenograft models in mice, cetuximab and irinotecan synergistically inhibited the growth of orthotopic anaplastic thyroid carcinoma xenografts in vitro and in vivo. Cetuximab potentiated the in vitro anti-proliferative and pro-apoptotic effect of irinotecan and achieved 93% in vivo inhibition of tumour growth when combined with irinotecan, compared to 77% and 79% inhibition when cetuximab and irinotecan were used alone, respectively. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein and a type I receptor tyrosine kinase expressed on both normal and malignant cells. It has been investigated as a therapeutic target for anticancer treatment, as it is often upregulated in cancer types, including head and neck, colon, and rectal cancers. When activated by its ligand, EGFR undergoes a conformational change and dimerization to form homodimers or heterodimers with another member of the ErbB family of receptors. Dimerization of EGFR activates the intracellular tyrosine kinase region of EGFR and promotes autophosphorylation, initiating a series of downstream signalling cascades, including cell differentiation, proliferation, migration, angiogenesis, and apoptosis. This EGFR signalling pathway is often dysregulated in cancer cells, leading to aberrant cell growth and enhanced cell survival. Cetuximab is a monoclonal antibody that binds specifically to the EGFR on both normal and tumour cells to competitively inhibit the binding of epidermal growth factor (EGF) and other ligands that are produced by normal and tumour tissue epithelial cells. Upon binding to domain III of EGFR - which is the binding site for its growth factor ligands - cetuximab prevents the receptor from adopting an extended conformation and thereby inhibits EGFR activation, as well as phosphorylation and activation of receptor-associated kinases (MAPK, PI3K/Akt, Jak/Stat). Inhibition of the EGFR signalling pathway ultimately leads to inhibition of cell cycle progression, cell survival pathways, and tumour cell motility and invasion. Cetuximab also induces cell apoptosis and decreases matrix metalloproteinase and vascular endothelial growth factor (VEGF) production. In vitro, cetuximab was shown to inhibit tumour angiogenesis. Binding of cetuximab to EGFR also results in internalization of the antibody-receptor complex, leading to an overall downregulation of EGFR expression. K-ras is a small G-protein downstream of EGFR that plays an important role in promoting the EGFR signalling cascade: in some malignant cells, K-ras can acquire activating mutations in exon 2 and thus be continuously active regardless of EGFR regulation. Since mutant Ras proteins can isolate the pathway from the effect of EGFR, K-Ras mutations can render EGFR inhibitors like cetuximab ineffective in exerting anti-tumour effects. Cetuximab is thus only limited in its use for K-Ras wild-type, EGFR-expressing cancers. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After administration of a 400 mg/m initial dose followed by a 250 mg/m weekly dose, the steady-state levels of cetuximab was reached by the third weekly infusion with mean peak and trough concentrations across studies ranging from 168 µg/mL to 235 µg/mL and 41 µg/mL to 85 µg/mL, respectively. T max is about 3 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of the distribution is about 2-3 L/m and is independent of dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Like other monoclonal antibodies, cetuximab is expected to undergo lysosomal degradation by the reticuloendothelial system and protein catabolism by a target‐mediated disposition pathway. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): There is limited information available. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): After administration of a 400 mg/m initial dose followed by a 250 mg/m weekly dose, the mean half-life for cetuximab was approximately 112 hours, with a range of 63 to 230 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck, the estimated clearance rate was 0.103 L/h. At doses ranging from 200 to 400 mg/m, complete saturation of systemic clearance was observed. In a population pharmacokinetic study, female patients had a 25% lower intrinsic cetuximab clearance than male patients, although there was no evidence of the need for dose modification based on sex. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The intravenous LD 50 is > 300 mg/kg in mice and > 200 mg/kg in rats. There is limited information on the overdose from cetuximab. In clinical trials, cetuximab was associated with serious and fatal infusion reactions, cardiopulmonary arrest or sudden death, and serious dermatologic toxicities. Pulmonary toxicities, such as interstitial lung disease, interstitial pneumonitis with non-cardiogenic pulmonary edema, and exacerbation of pre-existing fibrotic lung disease have been reported. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Erbitux •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cetuximab is an endothelial growth factor receptor binding fragment used to treat colorectal cancer as well as squamous cell carcinoma of the head and neck. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Cevimeline interact?

•Drug A: Adalimumab •Drug B: Cevimeline •Severity: MODERATE •Description: The metabolism of Cevimeline can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Muscarinic agonists such as cevimeline bind and activate the muscarinic M1 and M3 receptors. The M1 receptors are common in secretory glands (exocrine glands such as salivary and sweat glands), and their activation results in an increase in secretion from the secretory glands. The M3 receptors are found on smooth muscles and in many glands which help to stimulate secretion in salivary glands, and their activation generally results in smooth muscle contraction and increased glandular secretions. Therefore, as saliva excretion is increased, the symptoms of dry mouth are relieved. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly absorbed with peak concentration after 1.5 to 2 hours •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 6 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): < 20% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic, isozymes CYP2D6 and CYP3A4 are responsible for the metabolism of cevimeline. Approximately 44.5% of the drug is converted to cis and trans-sulfoxide, 22.3% to glucuronic acid conjugate, and 4% to N-oxide of cevimeline. Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 ± 1 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Evoxac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cevimelina Cévimèline Cevimeline Cevimelinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cevimeline is a muscarinic agonist with parasympathomimetic activities that is used for the symptomatic treatment of dry mouth in patients with Sjögren's Syndrome.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cevimeline interact? Information: •Drug A: Adalimumab •Drug B: Cevimeline •Severity: MODERATE •Description: The metabolism of Cevimeline can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Muscarinic agonists such as cevimeline bind and activate the muscarinic M1 and M3 receptors. The M1 receptors are common in secretory glands (exocrine glands such as salivary and sweat glands), and their activation results in an increase in secretion from the secretory glands. The M3 receptors are found on smooth muscles and in many glands which help to stimulate secretion in salivary glands, and their activation generally results in smooth muscle contraction and increased glandular secretions. Therefore, as saliva excretion is increased, the symptoms of dry mouth are relieved. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly absorbed with peak concentration after 1.5 to 2 hours •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 6 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): < 20% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic, isozymes CYP2D6 and CYP3A4 are responsible for the metabolism of cevimeline. Approximately 44.5% of the drug is converted to cis and trans-sulfoxide, 22.3% to glucuronic acid conjugate, and 4% to N-oxide of cevimeline. Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 ± 1 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Evoxac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cevimelina Cévimèline Cevimeline Cevimelinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cevimeline is a muscarinic agonist with parasympathomimetic activities that is used for the symptomatic treatment of dry mouth in patients with Sjögren's Syndrome. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Chikungunya vaccine (live, attenuated) interact?

•Drug A: Adalimumab •Drug B: Chikungunya vaccine (live, attenuated) •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Chikungunya vaccine (live, attenuated). •Extended Description: In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Summary not found

In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The severity of the interaction is minor.

Question: Does Adalimumab and Chikungunya vaccine (live, attenuated) interact? Information: •Drug A: Adalimumab •Drug B: Chikungunya vaccine (live, attenuated) •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Chikungunya vaccine (live, attenuated). •Extended Description: In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Summary not found Output: In a placebo-controlled clinical trial of patients with RA, no difference was detected in antipneumococcal antibody response between adalimumab and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with adalimumab. Similar proportions of patients developed protective levels of anti-influenza antibodies between adalimumab and placebo treatment groups; however, titers in aggregate to influenza antigens were moderately lower in patients receiving adalimumab. The severity of the interaction is minor.

Does Adalimumab and Chlorambucil interact?

•Drug A: Adalimumab •Drug B: Chlorambucil •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Chlorambucil. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For treatment of chronic lymphatic (lymphocytic) leukemia, childhood minimal-change nephrotic syndrome, and malignant lymphomas including lymphosarcoma, giant follicular lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas, and Waldenström’s Macroglobulinemia. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorambucil is an antineoplastic in the class of alkylating agents that is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard. The pharmacokinetic data suggests that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 1.5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Leukeran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambochlorin Chlorambucil Chloraminophen Clorambucilo •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorambucil is a chemotherapy agent used in the management of chronic lymphocytic leukemia and malignant lymphomas.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Chlorambucil interact? Information: •Drug A: Adalimumab •Drug B: Chlorambucil •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Chlorambucil. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For treatment of chronic lymphatic (lymphocytic) leukemia, childhood minimal-change nephrotic syndrome, and malignant lymphomas including lymphosarcoma, giant follicular lymphoma, Hodgkin's disease, non-Hodgkin's lymphomas, and Waldenström’s Macroglobulinemia. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorambucil is an antineoplastic in the class of alkylating agents that is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard. The pharmacokinetic data suggests that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 1.5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Leukeran •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ambochlorin Chlorambucil Chloraminophen Clorambucilo •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorambucil is a chemotherapy agent used in the management of chronic lymphocytic leukemia and malignant lymphomas. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Chloramphenicol interact?

•Drug A: Adalimumab •Drug B: Chloramphenicol •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Chloramphenicol. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Used in treatment of cholera, as it destroys the vibrios and decreases the diarrhea. It is effective against tetracycline-resistant vibrios. It is also used in eye drops or ointment to treat bacterial conjunctivitis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chloramphenicol is a broad-spectrum antibiotic that was derived from the bacterium Streptomyces venezuelae and is now produced synthetically. Chloramphenicol is effective against a wide variety of microorganisms, but due to serious side-effects (e.g., damage to the bone marrow, including aplastic anemia) in humans, it is usually reserved for the treatment of serious and life-threatening infections (e.g., typhoid fever). Chloramphenicol is bacteriostatic but may be bactericidal in high concentrations or when used against highly susceptible organisms. Chloramphenicol stops bacterial growth by binding to the bacterial ribosome (blocking peptidyl transferase) and inhibiting protein synthesis. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chloramphenicol is lipid-soluble, allowing it to diffuse through the bacterial cell membrane. It then reversibly binds to the L16 protein of the 50S subunit of bacterial ribosomes, where transfer of amino acids to growing peptide chains is prevented (perhaps by suppression of peptidyl transferase activity), thus inhibiting peptide bond formation and subsequent protein synthesis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly and completely absorbed from gastrointestinal tract following oral administration (bioavailability 80%). Well absorbed following intramuscular administration (bioavailability 70%). Intraocular and some systemic absorption also occurs after topical application to the eye. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding is 50-60% in adults and 32% is premature neonates. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, with 90% conjugated to inactive glucuronide. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Half-life in adults with normal hepatic and renal function is 1.5 - 3.5 hours. In patients with impaired renal function half-life is 3 - 4 hours. In patients with severely impaired hepatic function half-life is 4.6 - 11.6 hours. Half-life in children 1 month to 16 years old is 3 - 6.5 hours, while half-life in infants 1 to 2 days old is 24 hours or longer and is highly variable, especially in low birth-weight infants. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral, mouse: LD 50 = 1500 mg/kg; Oral, rat: LD 50 = 2500 mg/kg. Toxic reactions including fatalities have occurred in the premature and newborn; the signs and symptoms associated with these reactions have been referred to as the gray syndrome. Symptoms include (in order of appearance) abdominal distension with or without emesis, progressive pallid cyanosis, vasomotor collapse frequently accompanied by irregular respiration, and death within a few hours of onset of these symptoms. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Chloromycetin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chloramphénicol Chloramphenicol Chloramphenicolum Chlornitromycin Cloramfenicol Cloranfenicol Laevomycetinum Levomicetina Levomycetin •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chloramphenicol is a broad spectrum antibiotic that is effective against a variety of susceptible and serious bacterial infections but is not frequently used because of its high risk of bone marrow toxicity.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Chloramphenicol interact? Information: •Drug A: Adalimumab •Drug B: Chloramphenicol •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Chloramphenicol. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Used in treatment of cholera, as it destroys the vibrios and decreases the diarrhea. It is effective against tetracycline-resistant vibrios. It is also used in eye drops or ointment to treat bacterial conjunctivitis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chloramphenicol is a broad-spectrum antibiotic that was derived from the bacterium Streptomyces venezuelae and is now produced synthetically. Chloramphenicol is effective against a wide variety of microorganisms, but due to serious side-effects (e.g., damage to the bone marrow, including aplastic anemia) in humans, it is usually reserved for the treatment of serious and life-threatening infections (e.g., typhoid fever). Chloramphenicol is bacteriostatic but may be bactericidal in high concentrations or when used against highly susceptible organisms. Chloramphenicol stops bacterial growth by binding to the bacterial ribosome (blocking peptidyl transferase) and inhibiting protein synthesis. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chloramphenicol is lipid-soluble, allowing it to diffuse through the bacterial cell membrane. It then reversibly binds to the L16 protein of the 50S subunit of bacterial ribosomes, where transfer of amino acids to growing peptide chains is prevented (perhaps by suppression of peptidyl transferase activity), thus inhibiting peptide bond formation and subsequent protein synthesis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly and completely absorbed from gastrointestinal tract following oral administration (bioavailability 80%). Well absorbed following intramuscular administration (bioavailability 70%). Intraocular and some systemic absorption also occurs after topical application to the eye. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding is 50-60% in adults and 32% is premature neonates. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, with 90% conjugated to inactive glucuronide. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Half-life in adults with normal hepatic and renal function is 1.5 - 3.5 hours. In patients with impaired renal function half-life is 3 - 4 hours. In patients with severely impaired hepatic function half-life is 4.6 - 11.6 hours. Half-life in children 1 month to 16 years old is 3 - 6.5 hours, while half-life in infants 1 to 2 days old is 24 hours or longer and is highly variable, especially in low birth-weight infants. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral, mouse: LD 50 = 1500 mg/kg; Oral, rat: LD 50 = 2500 mg/kg. Toxic reactions including fatalities have occurred in the premature and newborn; the signs and symptoms associated with these reactions have been referred to as the gray syndrome. Symptoms include (in order of appearance) abdominal distension with or without emesis, progressive pallid cyanosis, vasomotor collapse frequently accompanied by irregular respiration, and death within a few hours of onset of these symptoms. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Chloromycetin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chloramphénicol Chloramphenicol Chloramphenicolum Chlornitromycin Cloramfenicol Cloranfenicol Laevomycetinum Levomicetina Levomycetin •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chloramphenicol is a broad spectrum antibiotic that is effective against a variety of susceptible and serious bacterial infections but is not frequently used because of its high risk of bone marrow toxicity. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Chloroquine interact?

•Drug A: Adalimumab •Drug B: Chloroquine •Severity: MODERATE •Description: The metabolism of Chloroquine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Chloroquine is indicated to treat infections of P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used to treat extraintestinal amebiasis. Chloroquine is also used off label for the treatment of rheumatic diseases, as well as treatment and prophylaxis of Zika virus. Chloroquine is currently undergoing clinical trials for the treatment of COVID-19. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin. Plasmodium species continue to accumulate toxic heme, killing the parasite. Chloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH. The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell. Chloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%. Intravenous chloroquine reaches a C max of 650-1300µg/L and oral chloroquine reaches a C max of 65-128µg/L with a T max of 0.5h. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of chloroquine is 200-800L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Chloroquine is 46-74% bound to plasma proteins. (-)-chloroquine binds more strongly to alpha-1-acid glycoprotein and (+)-chloroquine binds more strongly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine. It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1. N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Chloroquine is predominantly eliminated in the urine. 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half life of chloroquine is 20-60 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Chloroquine has a total plasma clearance of 0.35-1L/h/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, convulsions, respiratory arrest, cardiac arrest, and hypokalemia. Overdose should be managed with symptomatic and supportive treatment which may include prompt emesis, gastric lavage, and activated charcoal. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chloraquine Chlorochin Chloroquina Chloroquine Chloroquinium Chloroquinum Cloroquina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chloroquine is an antimalarial drug used to treat susceptible infections with P. vivax, P. malariae, P. ovale, and P. falciparum. It is also used for second line treatment for rheumatoid arthritis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Chloroquine interact? Information: •Drug A: Adalimumab •Drug B: Chloroquine •Severity: MODERATE •Description: The metabolism of Chloroquine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Chloroquine is indicated to treat infections of P. vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum. It is also used to treat extraintestinal amebiasis. Chloroquine is also used off label for the treatment of rheumatic diseases, as well as treatment and prophylaxis of Zika virus. Chloroquine is currently undergoing clinical trials for the treatment of COVID-19. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chloroquine inhibits the action of heme polymerase, which causes the buildup of toxic heme in Plasmodium species. It has a long duration of action as the half life is 20-60 days. Patients should be counselled regarding the risk of retinopathy with long term usage or high dosage, muscle weakness, and toxicity in children. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chloroquine inhibits the action of heme polymerase in malarial trophozoites, preventing the conversion of heme to hemazoin. Plasmodium species continue to accumulate toxic heme, killing the parasite. Chloroquine passively diffuses through cell membranes and into endosomes, lysosomes, and Golgi vesicles; where it becomes protonated, trapping the chloroquine in the organelle and raising the surrounding pH. The raised pH in endosomes, prevent virus particles from utilizing their activity for fusion and entry into the cell. Chloroquine does not affect the level of ACE2 expression on cell surfaces, but inhibits terminal glycosylation of ACE2, the receptor that SARS-CoV and SARS-CoV-2 target for cell entry. ACE2 that is not in the glycosylated state may less efficiently interact with the SARS-CoV-2 spike protein, further inhibiting viral entry. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Chloroquine oral solution has a bioavailability of 52-102% and oral tablets have a bioavailability of 67-114%. Intravenous chloroquine reaches a C max of 650-1300µg/L and oral chloroquine reaches a C max of 65-128µg/L with a T max of 0.5h. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of chloroquine is 200-800L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Chloroquine is 46-74% bound to plasma proteins. (-)-chloroquine binds more strongly to alpha-1-acid glycoprotein and (+)-chloroquine binds more strongly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Chloroquine is N-dealkylated primarily by CYP2C8 and CYP3A4 to N-desethylchloroquine. It is N-dealkylated to a lesser extent by CYP3A5, CYP2D6, and to an ever lesser extent by CYP1A1. N-desethylchloroquine can be further N-dealkylated to N-bidesethylchloroquine, which is further N-dealkylated to 7-chloro-4-aminoquinoline. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Chloroquine is predominantly eliminated in the urine. 50% of a dose is recovered in the urine as unchanged chloroquine, with 10% of the dose recovered in the urine as desethylchloroquine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half life of chloroquine is 20-60 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Chloroquine has a total plasma clearance of 0.35-1L/h/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Patients experiencing an overdose may present with headache, drowsiness, visual disturbances, nausea, vomiting, cardiovascular collapse, shock, convulsions, respiratory arrest, cardiac arrest, and hypokalemia. Overdose should be managed with symptomatic and supportive treatment which may include prompt emesis, gastric lavage, and activated charcoal. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chloraquine Chlorochin Chloroquina Chloroquine Chloroquinium Chloroquinum Cloroquina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chloroquine is an antimalarial drug used to treat susceptible infections with P. vivax, P. malariae, P. ovale, and P. falciparum. It is also used for second line treatment for rheumatoid arthritis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Chlorpheniramine interact?

•Drug A: Adalimumab •Drug B: Chlorpheniramine •Severity: MODERATE •Description: The metabolism of Chlorpheniramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed in the gastrointestinal tract. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 72% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via Cytochrome P450 (CYP450) enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 21-27 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral LD50 (rat): 306 mg/kg; Oral LD50 (mice): 130 mg/kg; Oral LD50 (guinea pig): 198 mg/kg [Registry of Toxic Effects of Chemical Substances. Ed. D. Sweet, US Dept. of Health & Human Services: Cincinatti, 2010.] Also a mild reproductive toxin to women of childbearing age. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aller-chlor, Allerest PE, Children's Nyquil Cold and Cough, Codar Ar, Coricidin Hbp Cold & Flu, Coricidin Hbp Cough and Cold, Dimetapp Long Acting Cough Plus Cold, Robitussin Pediatric Cough & Cold LA, Scot-tussin Sugar Free DM, Sudogest, Tussicaps, Tussionex, Tuxarin, Tuzistra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorophenylpyridamine Chlorphenamin Chlorphenamine Chlorphenaminum Chlorpheniramine Chlorpheniramine polistirex Chlorpheniraminum Clorfenamina Clorfeniramina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorpheniramine is a histamine-H1 receptor antagonist indicated for the management of symptoms associated with upper respiratory allergies.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Chlorpheniramine interact? Information: •Drug A: Adalimumab •Drug B: Chlorpheniramine •Severity: MODERATE •Description: The metabolism of Chlorpheniramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of rhinitis, urticaria, allergy, common cold, asthma and hay fever. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In allergic reactions an allergen interacts with and cross-links surface IgE antibodies on mast cells and basophils. Once the mast cell-antibody-antigen complex is formed, a complex series of events occurs that eventually leads to cell-degranulation and the release of histamine (and other chemical mediators) from the mast cell or basophil. Once released, histamine can react with local or widespread tissues through histamine receptors. Histamine, acting on H 1 -receptors, produces pruritis, vasodilatation, hypotension, flushing, headache, tachycardia, and bronchoconstriction. Histamine also increases vascular permeability and potentiates pain. Chlorpheniramine, is a histamine H1 antagonist (or more correctly, an inverse histamine agonist) of the alkylamine class. It competes with histamine for the normal H 1 -receptor sites on effector cells of the gastrointestinal tract, blood vessels and respiratory tract. It provides effective, temporary relief of sneezing, watery and itchy eyes, and runny nose due to hay fever and other upper respiratory allergies. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chlorpheniramine binds to the histamine H1 receptor. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed in the gastrointestinal tract. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 72% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily hepatic via Cytochrome P450 (CYP450) enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 21-27 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral LD50 (rat): 306 mg/kg; Oral LD50 (mice): 130 mg/kg; Oral LD50 (guinea pig): 198 mg/kg [Registry of Toxic Effects of Chemical Substances. Ed. D. Sweet, US Dept. of Health & Human Services: Cincinatti, 2010.] Also a mild reproductive toxin to women of childbearing age. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aller-chlor, Allerest PE, Children's Nyquil Cold and Cough, Codar Ar, Coricidin Hbp Cold & Flu, Coricidin Hbp Cough and Cold, Dimetapp Long Acting Cough Plus Cold, Robitussin Pediatric Cough & Cold LA, Scot-tussin Sugar Free DM, Sudogest, Tussicaps, Tussionex, Tuxarin, Tuzistra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorophenylpyridamine Chlorphenamin Chlorphenamine Chlorphenaminum Chlorpheniramine Chlorpheniramine polistirex Chlorpheniraminum Clorfenamina Clorfeniramina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorpheniramine is a histamine-H1 receptor antagonist indicated for the management of symptoms associated with upper respiratory allergies. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Chlorpromazine interact?

•Drug A: Adalimumab •Drug B: Chlorpromazine •Severity: MODERATE •Description: The metabolism of Chlorpromazine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of schizophrenia; to control nausea and vomiting; for relief of restlessness and apprehension before surgery; for acute intermittent porphyria; as an adjunct in the treatment of tetanus; to control the manifestations of the manic type of manic-depressive illness; for relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 20 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 90% to plasma proteins, primarily albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Kidneys, ~ 37% excreted in urine •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): ~ 30 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, restlessness •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpromazine Chlorpromazinum Clorpromazina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorpromazine is a phenothiazine antipsychotic used to treat nausea, vomiting, preoperative anxiety, schizophrenia, bipolar disorder, and severe behavioral problems in children.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Chlorpromazine interact? Information: •Drug A: Adalimumab •Drug B: Chlorpromazine •Severity: MODERATE •Description: The metabolism of Chlorpromazine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of schizophrenia; to control nausea and vomiting; for relief of restlessness and apprehension before surgery; for acute intermittent porphyria; as an adjunct in the treatment of tetanus; to control the manifestations of the manic type of manic-depressive illness; for relief of intractable hiccups; for the treatment of severe behavioral problems in children (1 to 12 years of age) marked by combativeness and/or explosive hyperexcitable behavior (out of proportion to immediate provocations), and in the short-term treatment of hyperactive children who show excessive motor activity with accompanying conduct disorders consisting of some or all of the following symptoms: impulsivity, difficulty sustaining attention, aggressivity, mood lability, and poor frustration tolerance. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorpromazine is a psychotropic agent indicated for the treatment of schizophrenia. It also exerts sedative and antiemetic activity. Chlorpromazine has actions at all levels of the central nervous system-primarily at subcortical levels-as well as on multiple organ systems. Chlorpromazine has strong antiadrenergic and weaker peripheral anticholinergic activity; ganglionic blocking action is relatively slight. It also possesses slight antihistaminic and antiserotonin activity. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chlorpromazine acts as an antagonist (blocking agent) on different postsysnaptic receptors -on dopaminergic-receptors (subtypes D1, D2, D3 and D4 - different antipsychotic properties on productive and unproductive symptoms), on serotonergic-receptors (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapypramidal side-effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), on histaminergic-receptors (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), alpha1/alpha2-receptors (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism - controversial) and finally on muscarinic (cholinergic) M1/M2-receptors (causing anticholinergic symptoms like dry mouth, blurred vision, obstipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side-effects). Additionally, Chlorpromazine is a weak presynaptic inhibitor of Dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Readily absorbed from the GI tract. Bioavailability varies due to first-pass metabolism by the liver. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 20 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): > 90% to plasma proteins, primarily albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver and kidneys. It is extensively metabolized by cytochrome P450 isozymes CYP2D6 (major pathway), CYP1A2 and CYP3A4. Approximately 10 to 12 major metabolite have been identified. Hydroxylation at positions 3 and 7 of the phenothiazine nucleus and the N-dimethylaminopropyl side chain undergoes demethylation and is also metabolized to an N-oxide. In urine, 20% of chlopromazine and its metabolites are excreted unconjugated in the urine as unchanged drug, demonomethylchlorpromazine, dedimethylchlorpromazine, their sulfoxide metabolites, and chlorpromazine-N-oxide. The remaining 80% consists of conjugated metabolites, principally O-glucuronides and small amounts of ethereal sulfates of the mono- and dihydroxy-derivatives of chlorpromazine and their sulfoxide metabolites. The major metabolites are the monoglucuronide of N-dedimethylchlorpromazine and 7-hydroxychlorpromazine. Approximately 37% of the administered dose of chlorpromazine is excreted in urine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Kidneys, ~ 37% excreted in urine •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): ~ 30 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, restlessness •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpromazine Chlorpromazinum Clorpromazina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorpromazine is a phenothiazine antipsychotic used to treat nausea, vomiting, preoperative anxiety, schizophrenia, bipolar disorder, and severe behavioral problems in children. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Chlorpropamide interact?

•Drug A: Adalimumab •Drug B: Chlorpropamide •Severity: MODERATE •Description: The metabolism of Chlorpropamide can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorpropamide, a second-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Chlorpropamide is twice as potent as the related second-generation agent glipizide. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Sulfonylureas such as chlorpropamide bind to ATP-sensitive potassium channels on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Readily absorbed from the GI tract. Peak plasma concentrations occur within 2-4 hours and the onset of action occurs within one hour. The maximal effect of chlorpropamide is seen 3-6 hours following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Highly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Up to 80% of dose is metabolized likely through the liver to to 2-hydroxylchlorpropamide (2-OH CPA), p-chlorobenzenesulfonylurea (CBSU), 3-hydroxylchlorpropamide (3-OH CPA), and p-chlorobenzenesulfonamide (CBSA); CBSA may be produced by decomposition in urine. It is unknown whether chlorpropamide metabolites exert hypoglycemic effects. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 80-90% of a single oral dose is excreted in the urine as unchaged drug and metabolites within 96 hours. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Approximately 36 hours with interindividual variation ranging from 25-60 hours. Duration of effect persists for at least 24 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): IPN-RAT LD 50 580 mg/kg •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpropamid Chlorpropamide Chlorpropamidum Clorpropamida •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorpropamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Chlorpropamide interact? Information: •Drug A: Adalimumab •Drug B: Chlorpropamide •Severity: MODERATE •Description: The metabolism of Chlorpropamide can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For treatment of NIDDM in conjunction with diet and exercise. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorpropamide, a second-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Chlorpropamide is twice as potent as the related second-generation agent glipizide. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Sulfonylureas such as chlorpropamide bind to ATP-sensitive potassium channels on the pancreatic cell surface, reducing potassium conductance and causing depolarization of the membrane. Depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which induces the secretion, or exocytosis, of insulin. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Readily absorbed from the GI tract. Peak plasma concentrations occur within 2-4 hours and the onset of action occurs within one hour. The maximal effect of chlorpropamide is seen 3-6 hours following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Highly bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Up to 80% of dose is metabolized likely through the liver to to 2-hydroxylchlorpropamide (2-OH CPA), p-chlorobenzenesulfonylurea (CBSU), 3-hydroxylchlorpropamide (3-OH CPA), and p-chlorobenzenesulfonamide (CBSA); CBSA may be produced by decomposition in urine. It is unknown whether chlorpropamide metabolites exert hypoglycemic effects. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 80-90% of a single oral dose is excreted in the urine as unchaged drug and metabolites within 96 hours. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Approximately 36 hours with interindividual variation ranging from 25-60 hours. Duration of effect persists for at least 24 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): IPN-RAT LD 50 580 mg/kg •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlorpropamid Chlorpropamide Chlorpropamidum Clorpropamida •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorpropamide is a sulfonylurea used in the treatment of non insulin dependent diabetes mellitus. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Chlorzoxazone interact?

•Drug A: Adalimumab •Drug B: Chlorzoxazone •Severity: MODERATE •Description: The metabolism of Chlorzoxazone can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the relief of discomfort associated with acute painful musculoskeletal conditions. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorzoxazone is a centrally-acting agent for painful musculoskeletal conditions. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex a.c. involved in producing and maintaining skeletal muscle spasm of varied etiology. The clinical result is a reduction of the skeletal muscle spasm with relief of pain and increased mobility of the involved muscles. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chlorzoxazone inhibits degranulation of mast cells, subsequently preventing the release of histamine and slow-reacting substance of anaphylaxis (SRS-A), mediators of type I allergic reactions. Chlorzoxazone also may reduce the release of inflammatory leukotrienes. Chlorzoxazone may act by inhibiting calcium and potassium influx which would lead to neuronal inhibition and muscle relaxation. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 13-18% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Chlorzoxazone is rapidly metabolized in the liver and is excreted in the urine, primarily in a conjugated form as the glucuronide. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Chlorzoxazone is rapidly metabolized and is excreted in the urine, primarily in a conjugated form as the glucuronide. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral, mouse: LD 50 = 440 mg/kg; Oral, rat: LD 50 = 763 mg/kg; Symptoms of overdose include diarrhea, dizziness, drowsiness, headache, light-headedness, nausea, and vomiting. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lorzone, Parafon Forte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-chlorobenzoxazolidone Chlorzoxane Chlorzoxazon Chlorzoxazona Chlorzoxazone Chlorzoxazonum Clorzoxazona Clorzoxazone •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorzoxazone is a drug with muscle relaxant properties that is used as an adjunct to physical therapy and analgesics to treat stiffness and pain caused by a variety of musculoskeletal conditions.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Chlorzoxazone interact? Information: •Drug A: Adalimumab •Drug B: Chlorzoxazone •Severity: MODERATE •Description: The metabolism of Chlorzoxazone can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the relief of discomfort associated with acute painful musculoskeletal conditions. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Chlorzoxazone is a centrally-acting agent for painful musculoskeletal conditions. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex a.c. involved in producing and maintaining skeletal muscle spasm of varied etiology. The clinical result is a reduction of the skeletal muscle spasm with relief of pain and increased mobility of the involved muscles. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chlorzoxazone inhibits degranulation of mast cells, subsequently preventing the release of histamine and slow-reacting substance of anaphylaxis (SRS-A), mediators of type I allergic reactions. Chlorzoxazone also may reduce the release of inflammatory leukotrienes. Chlorzoxazone may act by inhibiting calcium and potassium influx which would lead to neuronal inhibition and muscle relaxation. Data available from animal experiments as well as human study indicate that chlorzoxazone acts primarily at the level of the spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in producing and maintaining skeletal muscle spasm •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 13-18% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Chlorzoxazone is rapidly metabolized in the liver and is excreted in the urine, primarily in a conjugated form as the glucuronide. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Chlorzoxazone is rapidly metabolized and is excreted in the urine, primarily in a conjugated form as the glucuronide. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral, mouse: LD 50 = 440 mg/kg; Oral, rat: LD 50 = 763 mg/kg; Symptoms of overdose include diarrhea, dizziness, drowsiness, headache, light-headedness, nausea, and vomiting. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lorzone, Parafon Forte •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-chlorobenzoxazolidone Chlorzoxane Chlorzoxazon Chlorzoxazona Chlorzoxazone Chlorzoxazonum Clorzoxazona Clorzoxazone •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Chlorzoxazone is a drug with muscle relaxant properties that is used as an adjunct to physical therapy and analgesics to treat stiffness and pain caused by a variety of musculoskeletal conditions. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Ciclesonide interact?

•Drug A: Adalimumab •Drug B: Ciclesonide •Severity: MODERATE •Description: The metabolism of Ciclesonide can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound. The precise mechanism through which ciclesonide affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic inflammation. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Glucocorticoids such as ciclesonide can inhibit leukocyte infiltration at the site of inflammation, interfere with mediators of inflammatory response, and suppress humoral immune responses. The antiinflammatory actions of glucocorticoids are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Ciclesonide reduces inflammatory reaction by limiting the capillary dilatation and permeability of the vascular structures. These compounds restrict the accumulation of polymorphonuclear leukocytes and macrophages and reduce the release of vasoactive kinins. Recent research suggests that corticosteroids may inhibit the release of arachidonic acid from phospholipids, thereby reducing the formation of prostaglandins. Ciclesonide is a glucocorticoid receptor agonist. On binding, the corticoreceptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing an increase or decrease in expression of specific target genes, including suppression of IL2 (interleukin 2) expression. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. The intranasal administration of ciclesonide at recommended doses results in negligible serum concentrations of ciclesonide. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged ≥ 99% each, with ≤ 1% of unbound drug detected in the systemic circulation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Des-ciclesonide undergoes metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 152 L/hr [Following IV administration of 800 mcg of ciclesonide] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Alvesco, Omnaris, Zetonna •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Ciclesonide is a glucocorticoid used in the symptomatic relief of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Ciclesonide interact? Information: •Drug A: Adalimumab •Drug B: Ciclesonide •Severity: MODERATE •Description: The metabolism of Ciclesonide can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents 12 years of age and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Ciclesonide is a pro-drug that is enzymatically hydrolyzed to a pharmacologically active metabolite, C21-desisobutyryl-ciclesonide (des-ciclesonide or RM1) following intranasal application. Des-ciclesonide has anti-inflammatory activity with affinity for the glucocorticoid receptor that is 120 times higher than the parent compound. The precise mechanism through which ciclesonide affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic inflammation. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Glucocorticoids such as ciclesonide can inhibit leukocyte infiltration at the site of inflammation, interfere with mediators of inflammatory response, and suppress humoral immune responses. The antiinflammatory actions of glucocorticoids are thought to involve phospholipase A2 inhibitory proteins, lipocortins, which control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. Ciclesonide reduces inflammatory reaction by limiting the capillary dilatation and permeability of the vascular structures. These compounds restrict the accumulation of polymorphonuclear leukocytes and macrophages and reduce the release of vasoactive kinins. Recent research suggests that corticosteroids may inhibit the release of arachidonic acid from phospholipids, thereby reducing the formation of prostaglandins. Ciclesonide is a glucocorticoid receptor agonist. On binding, the corticoreceptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements (GRE) in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing an increase or decrease in expression of specific target genes, including suppression of IL2 (interleukin 2) expression. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Ciclesonide and des-ciclesonide have negligible oral bioavailability (both less than 1%) due to low gastrointestinal absorption and high first-pass metabolism. The intranasal administration of ciclesonide at recommended doses results in negligible serum concentrations of ciclesonide. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The percentage of ciclesonide and des-ciclesonide bound to human plasma proteins averaged ≥ 99% each, with ≤ 1% of unbound drug detected in the systemic circulation. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Des-ciclesonide undergoes metabolism in the liver to additional metabolites mainly by the cytochrome P450 (CYP) 3A4 isozyme and to a lesser extent by CYP 2D6. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 152 L/hr [Following IV administration of 800 mcg of ciclesonide] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Alvesco, Omnaris, Zetonna •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Ciclesonide is a glucocorticoid used in the symptomatic relief of nasal symptoms associated with seasonal and perennial allergic rhinitis in adults and adolescents. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cilostazol interact?

•Drug A: Adalimumab •Drug B: Cilostazol •Severity: MODERATE •Description: The metabolism of Cilostazol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated for the alleviation of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest). •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cilostazol reduces the symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C max and a 25% increase in AUC. Absolute bioavailability is not known. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95-98% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-trans-hydroxy-cilostazol. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 11-13 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Information on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD 50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cilostazol Cilostazole Cilostazolum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cilostazol is an antiplatelet agent and vasodilator used for the symptomatic relief of intermittent claudication.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cilostazol interact? Information: •Drug A: Adalimumab •Drug B: Cilostazol •Severity: MODERATE •Description: The metabolism of Cilostazol can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated for the alleviation of symptoms of intermittent claudication (pain in the legs that occurs with walking and disappears with rest). •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cilostazol reduces the symptoms of intermittent claudication, as indicated by an increased walking distance. Intermittent claudication is pain in the legs that occurs with walking and disappears with rest. The pain occurs due to reduced blood flow to the legs. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in C max and a 25% increase in AUC. Absolute bioavailability is not known. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 95-98% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4'-trans-hydroxy-cilostazol. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 11-13 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Information on acute overdosage with cilostazol in humans is limited. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: severe headache, diarrhea, hypotension, tachycardia, and possibly cardiac arrhythmias. The oral LD 50 of cilostazol is >5.0 g/kg in mice and rats and >2.0 g/kg in dogs. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cilostazol Cilostazole Cilostazolum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cilostazol is an antiplatelet agent and vasodilator used for the symptomatic relief of intermittent claudication. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cinacalcet interact?

•Drug A: Adalimumab •Drug B: Cinacalcet •Severity: MODERATE •Description: The metabolism of Cinacalcet can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease who are on hemodialysis or peritoneal dialysis. Also for the treatment of hypercalcemia in patients with parathyroid carcinoma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 1000 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 93 to 97% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ß-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Terminal half-life is 30 to 40 hours. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of cinacalcet may lead to hypocalcemia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Mimpara, Sensipar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinacalcet •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cinacalcet is a calcium sensing receptor agonist used to treat secondary hyperparathyroidism in chronic kidney disease and hypercalcemia in parathyroid carcinoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cinacalcet interact? Information: •Drug A: Adalimumab •Drug B: Cinacalcet •Severity: MODERATE •Description: The metabolism of Cinacalcet can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of secondary hyperparathyroidism in patients with Chronic Kidney Disease who are on hemodialysis or peritoneal dialysis. Also for the treatment of hypercalcemia in patients with parathyroid carcinoma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cinacalcet is a drug that acts as a calcimimetic (i.e. it mimics the action of calcium on tissues). Secondary hyperparathyroidism (HPT) in patients with chronic kidney disease (CKD) is a progressive disease, associated with increases in parathyroid hormone (PTH) levels and derangements in calcium and phosphorus metabolism. Increased PTH stimulates osteoclastic activity resulting in cortical bone resorption and marrow fibrosis. The goals of treatment of secondary hyperparathyroidism are to lower levels of PTH, calcium, and phosphorus in the blood, in order to prevent progressive bone disease and the systemic consequences of disordered mineral metabolism. In CKD patients on dialysis with uncontrolled secondary HPT, reductions in PTH are associated with a favorable impact on bone-specific alkaline phosphatase (BALP), bone turnover and bone fibrosis. Cinacalcet reduces calcium levels by increasing the sensitivity of the calcium sensing receptor to extracellular calcium. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cinacalcet directly lowers parathyroid hormone levels by increasing the sensitivity of the calcium sensing receptors to activation by extracellular calcium, resulting in the inhibition of PTH secretion. The reduction in PTH is associated with a concomitant decrease in serum calcium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Rapidly absorbed following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 1000 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 93 to 97% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism is hepatic by multiple enzymes, primarily CYP3A4, CYP2D6, and CYP1A2. After administration of a 75 mg radiolabeled dose to healthy volunteers, cinacalcet was rapidly and extensively metabolized via: 1) oxidative N-dealkylation to hydrocinnamic acid and hydroxy-hydrocinnamic acid, which are further metabolized via ß-oxidation and glycine conjugation; the oxidative N-dealkylation process also generates metabolites that contain the naphthalene ring; and 2) oxidation of the naphthalene ring on the parent drug to form dihydrodiols, which are further conjugated with glucuronic acid. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cinacalcet is metabolized by multiple enzymes, primarily CYP3A4, CYP2D6 and CYP1A2. Renal excretion of metabolites was the primary route of elimination of radioactivity. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Terminal half-life is 30 to 40 hours. The mean half-life of cinacalcet is prolonged by 33% and 70% in patients with moderate and severe hepatic impairment, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Doses titrated up to 300 mg once daily have been safely administered to patients on dialysis. Overdosage of cinacalcet may lead to hypocalcemia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Mimpara, Sensipar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinacalcet •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cinacalcet is a calcium sensing receptor agonist used to treat secondary hyperparathyroidism in chronic kidney disease and hypercalcemia in parathyroid carcinoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cinnarizine interact?

•Drug A: Adalimumab •Drug B: Cinnarizine •Severity: MODERATE •Description: The metabolism of Cinnarizine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of vertigo/meniere's disease, nausea and vomiting, motion sickness and also useful for vestibular symptoms of other origins. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinarizina Cinnarizine Cinnarizinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cinnarizine is a drug used for the management of labyrinthine disorder symptoms, including vertigo, tinnitus, nystagmus, nausea, and vomiting.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cinnarizine interact? Information: •Drug A: Adalimumab •Drug B: Cinnarizine •Severity: MODERATE •Description: The metabolism of Cinnarizine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of vertigo/meniere's disease, nausea and vomiting, motion sickness and also useful for vestibular symptoms of other origins. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cinarizina Cinnarizine Cinnarizinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cinnarizine is a drug used for the management of labyrinthine disorder symptoms, including vertigo, tinnitus, nystagmus, nausea, and vomiting. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cisapride interact?

•Drug A: Adalimumab •Drug B: Cisapride •Severity: MODERATE •Description: The metabolism of Cisapride can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cisapride is a parasympathomimetic which acts as a serotonin 5-HT 4 agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cisapride acts through the stimulation of the serotonin 5-HT 4 receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97.5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 6-12 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cisapride is a medication used to treat heartburn associated with GERD.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cisapride interact? Information: •Drug A: Adalimumab •Drug B: Cisapride •Severity: MODERATE •Description: The metabolism of Cisapride can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the symptomatic treatment of adult patients with nocturnal heartburn due to gastroesophageal reflux disease. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cisapride is a parasympathomimetic which acts as a serotonin 5-HT 4 agonist; upon activation of the receptor signaling pathway, cisapride promotes the release of acetylcholine neurotransmitters in the enteric nervous system. Cisapride stimulates motility of the upper gastrointestinal tract without stimulating gastric, biliary, or pancreatic secretions. Cisapride increases the tone and amplitude of gastric (especially antral) contractions, relaxes the pyloric sphincter and the duodenal bulb, and increases peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. It increases the resting tone of the lower esophageal sphincter. It has little, if any, effect on the motility of the colon or gallbladder. Cisapride does not induce muscarinic or nicotinic receptor stimulation, nor does it inhibit acetylcholinesterase activity. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cisapride acts through the stimulation of the serotonin 5-HT 4 receptors which increases acetylcholine release in the enteric nervous system (specifically the myenteric plexus). This results in increased tone and amplitude of gastric (especially antral) contractions, relaxation of the pyloric sphincter and the duodenal bulb, and increased peristalsis of the duodenum and jejunum resulting in accelerated gastric emptying and intestinal transit. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Cisapride is rapidly absorbed after oral administration, with an absolute bioavailability of 35-40%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97.5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Extensively metabolized via cytochrome P450 3A4 enzyme. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 6-12 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cisapride is a medication used to treat heartburn associated with GERD. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cisplatin interact?

•Drug A: Adalimumab •Drug B: Cisplatin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cisplatin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of metastatic testicular tumors, metastatic ovarian tumors and advanced bladder cancer. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cisplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following cisplatin doses of 20 to 120 mg/m^2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Volume of distribution at steady state = 11-12 L/m^2 •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cisplatin does not undergo instantaneous and reversible binding to plasma protein that is characteristic of normal drug-protein binding. However, the platinum itself is capable of binding to plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The parent compound, cisplatin, is excreted in the urine. Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Cisplatin decays monoexponentially with a half life of 20 to 30 minutes following administrations of 50 or 100 mg/m^2. Cisplatin has a plasma half-life of 30 minutes. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 15-16 L/h/m^2 [total body clearance, 7-hour infusion of 100 mg/m^2] 62 mL/min/m^2 [renal clearance, 2-hour infusion of 100 mg/m^2] 50 mL/min/m^2 [renal clearance, 6- to 7-hour infusion of 100 mg/m^2] The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Platinol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (SP-4-2)-DIAMMINEDICHLOROPLATINUM CDDP Cis-DDP CIS-DIAMMINEDICHLOROPLATINUM CIS-DIAMMINEDICHLOROPLATINUM II Cisplatin cisplatino INT-230-6 COMPONENT CISPLATIN INT230-6 COMPONENT CISPLATIN PLATINUM, DIAMMINEDICHLORO-, (SP-4-2)- •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cisplatin is a platinum based chemotherapy agent used to treat various sarcomas, carcinomas, lymphomas, and germ cell tumors.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Cisplatin interact? Information: •Drug A: Adalimumab •Drug B: Cisplatin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cisplatin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of metastatic testicular tumors, metastatic ovarian tumors and advanced bladder cancer. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cisplatin is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following cisplatin doses of 20 to 120 mg/m^2, the concentrations of platinum are highest in liver, prostate, and kidney; somewhat lower in bladder, muscle, testicle, pancreas, and spleen; and lowest in bowel, adrenal, heart, lung, cerebrum, and cerebellum. Platinum is present in tissues for as long as 180 days after the last administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Volume of distribution at steady state = 11-12 L/m^2 •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cisplatin does not undergo instantaneous and reversible binding to plasma protein that is characteristic of normal drug-protein binding. However, the platinum itself is capable of binding to plasma proteins, including albumin, transferrin, and gamma globulin. Three hours after a bolus injection and two hours after the end of a three-hour infusion, 90% of the plasma platinum is protein bound. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The parent compound, cisplatin, is excreted in the urine. Although small amounts of platinum are present in the bile and large intestine after administration of cisplatin, the fecal excretion of platinum appears to be insignificant. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Cisplatin decays monoexponentially with a half life of 20 to 30 minutes following administrations of 50 or 100 mg/m^2. Cisplatin has a plasma half-life of 30 minutes. The complexes between albumin and the platinum from cisplatin do not dissociate to a significant extent and are slowly eliminated with a minimum half-life of five days or more. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 15-16 L/h/m^2 [total body clearance, 7-hour infusion of 100 mg/m^2] 62 mL/min/m^2 [renal clearance, 2-hour infusion of 100 mg/m^2] 50 mL/min/m^2 [renal clearance, 6- to 7-hour infusion of 100 mg/m^2] The renal clearance of free (ultrafilterable) platinum also exceeds the glomerular filtration rate indicating that cisplatin or other platinum-containing molecules are actively secreted by the kidneys. The renal clearance of free platinum is nonlinear and variable and is dependent on dose, urine flow rate, and individual variability in the extent of active secretion and possible tubular reabsorption. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Platinol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (SP-4-2)-DIAMMINEDICHLOROPLATINUM CDDP Cis-DDP CIS-DIAMMINEDICHLOROPLATINUM CIS-DIAMMINEDICHLOROPLATINUM II Cisplatin cisplatino INT-230-6 COMPONENT CISPLATIN INT230-6 COMPONENT CISPLATIN PLATINUM, DIAMMINEDICHLORO-, (SP-4-2)- •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cisplatin is a platinum based chemotherapy agent used to treat various sarcomas, carcinomas, lymphomas, and germ cell tumors. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Citalopram interact?

•Drug A: Adalimumab •Drug B: Citalopram •Severity: MODERATE •Description: The metabolism of Citalopram can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Citalopram is approved by the FDA for treating adults with major depressive disorder. It has also been used off-label to treat various diseases, including but not limited to sexual dysfunction, ethanol abuse, psychiatric conditions such as obsessive-compulsive disorder (OCD), social anxiety disorder, panic disorder, and diabetic neuropathy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Citalopram belongs to a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). It has been found to relieve or manage symptoms of depression, anxiety, eating disorders and obsessive-compulsive disorder among other mood disorders. The antidepressant, anti-anxiety, and other actions of citalopram are linked to its inhibition of CNS central uptake of serotonin. Serotonergic abnormalities have been reported in patients with mood disorders. Behavioral and neuropsychological effects of serotonin include the regulation of mood, perception, reward, anger, aggression, appetite, memory, sexuality, and attention, as examples. The onset of action for depression is approximately 1 to 4 weeks. The complete response may take 8-12 weeks after initiation of citalopram. In vitro studies demonstrate that citalopram is a strong and selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine central reuptake. The chronic administration of citalopram has been shown to downregulate central norepinephrine receptors, similar to other drugs effective in the treatment of major depressive disorder. Citalopram does not inhibit monoamine oxidase. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of citalopram is unclear but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT), potentially through the inhibition of the serotonin transporter (solute carrier family 6 member 4, SLC6A4 ). Citalopram binds with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs. Particularly, citalopram has no or very low affinity for 5-HT 1A, 5-HT 2A, dopamine D 1 and D 2, α 1 -, α 2 -, and β-adrenergic, histamine H 1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of citalopram is about 12 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Citalopram is metabolized mainly in the liver via N -demethylation to its main metabolite, demethylcitalopram by CYP2C19 and CYP3A4. Other metabolites include didemethylcitalopram via CYP2D6 metabolism, citalopram N -oxide and propionic acid derivative via monoamine oxidase enzymes A and B and aldehyde oxidase. Citalopram metabolites exert little pharmacologic activity in comparison to the parent drug and are not likely to contribute to the clinical effect of citalopram. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 12 to 23% of an oral dose of citalopram is found unchanged in the urine, while 10% is found in feces. Following intravenous administrations of citalopram, the fraction of the drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean terminal half-life of citalopram is about 35 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including citalopram, during pregnancy. There also are risks associated with untreated depression in pregnancy. Citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the Maximum Recommended Human Dose (MRHD) of 40 mg, based on mg/m2 body surface area. Citalopram caused maternal toxicity of CNS clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the MRHD. At this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). The no observed adverse effect level (NOAEL) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the MRHD. Citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the MRHD of 40 mg, based on mg/m2 body surface area. No maternal or embryofetal toxicity was observed. The NOAEL for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the MRHD. Citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 40 mg, based on mg/m2 body surface area. Citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the MRHD. The NOAEL for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the MRHD. In a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the MRHD. A NOAEL was not determined in that study. SSRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction. The following have been reported with citalopram tablet overdosage: • Seizures, which may be delayed, and altered mental status including coma. • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension is most commonly seen, but hypotension can rarely be seen alone or with co‐ingestants including alcohol. • Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk). Prolonged cardiac monitoring is recommended in citalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a citalopram overdose. Consider contacting a Poison Center (1‐800‐221‐2222) or a medical toxicologist for additional overdosage management recommendations. Citalopram increased the incidence of small intestine carcinoma in rats treated for 24 months at doses of 8 and 24 mg/kg/day in the diet, which are approximately 2 and 6 times the Maximum Recommended Human Dose (MRHD) of 40 mg, respectively, based on mg/m2 body surface area. A no-effect level (NOEL) for this finding was not established. Citalopram did not increase the incidence of tumors in mice treated for 18 months at doses up to 240 mg/kg/day in the diet, which is approximately 30 times the MRDH of 40 mg based on mg/m2 body surface area. Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays. Citalopram was administered orally to female and male rats at doses of 32, 48, and 72 mg/kg/day prior to and throughout mating and continuing to gestation. These doses are approximately 8, 12, and 17 times the MRHD of 40 mg based on mg/m2 body surface area. Mating and fertility were decreased at doses ≥ 32 mg/kg/day, which is approximately 8 times the MRHD. Gestation duration was increased to 48 mg/kg/day, which is approximately 12 times the MRHD. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Celexa, Ctp •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Citalopram is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Citalopram interact? Information: •Drug A: Adalimumab •Drug B: Citalopram •Severity: MODERATE •Description: The metabolism of Citalopram can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Citalopram is approved by the FDA for treating adults with major depressive disorder. It has also been used off-label to treat various diseases, including but not limited to sexual dysfunction, ethanol abuse, psychiatric conditions such as obsessive-compulsive disorder (OCD), social anxiety disorder, panic disorder, and diabetic neuropathy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Citalopram belongs to a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). It has been found to relieve or manage symptoms of depression, anxiety, eating disorders and obsessive-compulsive disorder among other mood disorders. The antidepressant, anti-anxiety, and other actions of citalopram are linked to its inhibition of CNS central uptake of serotonin. Serotonergic abnormalities have been reported in patients with mood disorders. Behavioral and neuropsychological effects of serotonin include the regulation of mood, perception, reward, anger, aggression, appetite, memory, sexuality, and attention, as examples. The onset of action for depression is approximately 1 to 4 weeks. The complete response may take 8-12 weeks after initiation of citalopram. In vitro studies demonstrate that citalopram is a strong and selective inhibitor of neuronal serotonin reuptake and has weak effects on norepinephrine and dopamine central reuptake. The chronic administration of citalopram has been shown to downregulate central norepinephrine receptors, similar to other drugs effective in the treatment of major depressive disorder. Citalopram does not inhibit monoamine oxidase. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of citalopram is unclear but is presumed to be related to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT), potentially through the inhibition of the serotonin transporter (solute carrier family 6 member 4, SLC6A4 ). Citalopram binds with significantly less affinity to histamine, acetylcholine, and norepinephrine receptors than tricyclic antidepressant drugs. Particularly, citalopram has no or very low affinity for 5-HT 1A, 5-HT 2A, dopamine D 1 and D 2, α 1 -, α 2 -, and β-adrenergic, histamine H 1, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 40 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of citalopram is about 12 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Citalopram is metabolized mainly in the liver via N -demethylation to its main metabolite, demethylcitalopram by CYP2C19 and CYP3A4. Other metabolites include didemethylcitalopram via CYP2D6 metabolism, citalopram N -oxide and propionic acid derivative via monoamine oxidase enzymes A and B and aldehyde oxidase. Citalopram metabolites exert little pharmacologic activity in comparison to the parent drug and are not likely to contribute to the clinical effect of citalopram. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 12 to 23% of an oral dose of citalopram is found unchanged in the urine, while 10% is found in feces. Following intravenous administrations of citalopram, the fraction of the drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean terminal half-life of citalopram is about 35 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Based on data from published observational studies, exposure to SSRIs, particularly in the month before delivery, has been associated with a less than 2-fold increase in the risk of postpartum hemorrhage. Available data from published epidemiologic studies and postmarketing reports with citalopram use in pregnancy have not established an increased risk of major birth defects or miscarriage. Published studies demonstrated that citalopram levels in both cord blood and amniotic fluid are similar to those observed in maternal serum. There are risks of persistent pulmonary hypertension of the newborn (PPHN) and/or poor neonatal adaptation with exposure to selective serotonin reuptake inhibitors (SSRIs), including citalopram, during pregnancy. There also are risks associated with untreated depression in pregnancy. Citalopram was administered orally to pregnant rats during the period of organogenesis at doses of 32, 56, and 112 mg/kg/day, which are approximately 8, 14, and 27 times the Maximum Recommended Human Dose (MRHD) of 40 mg, based on mg/m2 body surface area. Citalopram caused maternal toxicity of CNS clinical signs and decreased weight gain at 112 mg/kg/day, which is 27 times the MRHD. At this maternally toxic dose, citalopram decreased embryo/fetal growth and survival and increased fetal abnormalities (including cardiovascular and skeletal defects). The no observed adverse effect level (NOAEL) for maternal and embryofetal toxicity is 56 mg/kg/day, which is approximately 14 times the MRHD. Citalopram was administered orally to pregnant rabbits during the period of organogenesis at doses up to 16 mg/kg/day, which is approximately 8 times the MRHD of 40 mg, based on mg/m2 body surface area. No maternal or embryofetal toxicity was observed. The NOAEL for maternal and embryofetal toxicity is 16 mg/kg/day, which is approximately 8 times the MRHD. Citalopram was administered orally to pregnant rats during late gestation and lactation periods at doses of 4.8, 12.8, and 32 mg/kg/day, which are approximately 1, 3, and 8 times the MRHD of 40 mg, based on mg/m2 body surface area. Citalopram increased offspring mortality during the first 4 days of birth and decreased offspring growth at 32 mg/kg/day, which is approximately 8 times the MRHD. The NOAEL for developmental toxicity is 12.8 mg/kg/day, which is approximately 3 times the MRHD. In a separate study, similar effects on offspring mortality and growth were seen when dams were treated throughout gestation and early lactation at doses ≥ 24 mg/kg/day, which is approximately 6 times the MRHD. A NOAEL was not determined in that study. SSRIs, including citalopram, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse reaction. The following have been reported with citalopram tablet overdosage: • Seizures, which may be delayed, and altered mental status including coma. • Cardiovascular toxicity, which may be delayed, including QRS and QTc interval prolongation, wide complex tachyarrhythmias, and torsade de pointes. Hypertension is most commonly seen, but hypotension can rarely be seen alone or with co‐ingestants including alcohol. • Serotonin syndrome (patients with a multiple drug overdosage with other pro-serotonergic drugs may have a higher risk). Prolonged cardiac monitoring is recommended in citalopram overdosage ingestions due to the arrhythmia risk. Gastrointestinal decontamination with activated charcoal should be considered in patients who present early after a citalopram overdose. Consider contacting a Poison Center (1‐800‐221‐2222) or a medical toxicologist for additional overdosage management recommendations. Citalopram increased the incidence of small intestine carcinoma in rats treated for 24 months at doses of 8 and 24 mg/kg/day in the diet, which are approximately 2 and 6 times the Maximum Recommended Human Dose (MRHD) of 40 mg, respectively, based on mg/m2 body surface area. A no-effect level (NOEL) for this finding was not established. Citalopram did not increase the incidence of tumors in mice treated for 18 months at doses up to 240 mg/kg/day in the diet, which is approximately 30 times the MRDH of 40 mg based on mg/m2 body surface area. Citalopram was mutagenic in the in vitro bacterial reverse mutation assay (Ames test) in 2 of 5 bacterial strains (Salmonella TA98 and TA1537) in the absence of metabolic activation. It was clastogenic in the in vitro Chinese hamster lung cell assay for chromosomal aberrations in the presence and absence of metabolic activation. Citalopram was not mutagenic in the in vitro mammalian forward gene mutation assay (HPRT) in mouse lymphoma cells or in in vitro/in vivo unscheduled DNA synthesis (UDS) assay in rat liver. It was not clastogenic in the in vitro chromosomal aberration assay in human lymphocytes or in two in vivo mouse micronucleus assays. Citalopram was administered orally to female and male rats at doses of 32, 48, and 72 mg/kg/day prior to and throughout mating and continuing to gestation. These doses are approximately 8, 12, and 17 times the MRHD of 40 mg based on mg/m2 body surface area. Mating and fertility were decreased at doses ≥ 32 mg/kg/day, which is approximately 8 times the MRHD. Gestation duration was increased to 48 mg/kg/day, which is approximately 12 times the MRHD. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Celexa, Ctp •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Citalopram is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cladribine interact?

•Drug A: Adalimumab •Drug B: Cladribine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cladribine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established. Cladribine also has therapeutic effects in patients with multiple sclerosis; although the mechanism of action for this therapeutic effect is not fully elucidated, it is thought to involve cytotoxic effects on B and T lymphocytes by impairing DNA synthesis which in turn results in depletion of lymphocytes. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Oral bioavailability is 34 to 48%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 4.5 ± 2.8 L/kg [patients with hematologic malignancies] 9 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5.4 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 978 +/- 422 mL/h/kg •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Litak, Mavenclad •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-CdA 2-chloro-deoxyadenosine 2-Chlorodeoxyadenosine 2ClAdo Cladribina Cladribine Cladribinum CldAdo •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cladribine is a purine antimetabolite used for the management of relapsing forms of Multiple Sclerosis (MS), used in patients who have not responded to or who were unable to tolerate alternative MS drugs.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Cladribine interact? Information: •Drug A: Adalimumab •Drug B: Cladribine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cladribine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of active hairy cell leukemia (leukemic reticuloendotheliosis) as defined by clinically significant anemia, neutropenia, thrombocytopenia, or disease-related symptoms. Also used as an alternative agent for the treatment of chronic lymphocytic leukemia (CLL), low-grade non-Hodgkin's lymphoma, and cutaneous T-cell lymphoma. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cladribine is a synthetic purine nucleoside that acts as an antineoplastic agent with immunosuppressive effects. Cladribine differs structurally from deoxyadenosine only by the presence of a chlorine atom at position 2 of the purine ring, which results in resistance to enzymatic degradation by adenosine deaminase. Due to this resistance, cladribine exhibits a more prolonged cytotoxic effect than deoxyadenosine against resting and proliferating lymphocytes. Cladribine is one of a group of chemotherapy drugs known as the anti-metabolites. Anti-metabolites stop cells from making and repairing DNA, which are processes that are necessary for cancer cells to grow and multiply. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cladribine is structurally related to fludarabine and pentostatin but has a different mechanism of action. Although the exact mechanism of action has not been fully determined, evidence shows that cladribine is phosphorylated by deoxycytidine kinase to the nucleotidecladribine triphosphate (CdATP; 2-chloro-2′-deoxyadenosine 5′-triphosphate), which accumulates and is incorporated into DNA in cells such as lymphocytes that contain high levels of deoxycytidine kinase and low levels of deoxynucleotidase, resulting in DNA strand breakage and inhibition of DNA synthesis and repair. High levels of CdATP also appear to inhibit ribonucleotide reductase, which leads to an imbalance in triphosphorylated deoxynucleotide (dNTP) pools and subsequent DNA strand breaks, inhibition of DNA synthesis and repair, nicotinamide adenine dinucleotide (NAD) and ATP depletion, and cell death. Unlike other antimetabolite drugs, cladribine has cytotoxic effects on resting as well as proliferating lymphocytes. However, it does cause cells to accumulate at the G1/S phase junction, suggesting that cytotoxicity is associated with events critical to cell entry into S phase. It also binds purine nucleoside phosphorylase (PNP), however no relationship between this binding and a mechanism of action has been established. Cladribine also has therapeutic effects in patients with multiple sclerosis; although the mechanism of action for this therapeutic effect is not fully elucidated, it is thought to involve cytotoxic effects on B and T lymphocytes by impairing DNA synthesis which in turn results in depletion of lymphocytes. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Oral bioavailability is 34 to 48%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 4.5 ± 2.8 L/kg [patients with hematologic malignancies] 9 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized in all cells with deoxycytidine kinase activity to 2-chloro-2'-deoxyadenosine-5'-triphosphate •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5.4 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 978 +/- 422 mL/h/kg •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of overdose include irreversible neurologic toxicity (paraparesis/quadriparesis), acute nephrotoxicity, and severe bone marrow suppression resulting in neutropenia, anemia and thrombocytopenia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Litak, Mavenclad •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-CdA 2-chloro-deoxyadenosine 2-Chlorodeoxyadenosine 2ClAdo Cladribina Cladribine Cladribinum CldAdo •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cladribine is a purine antimetabolite used for the management of relapsing forms of Multiple Sclerosis (MS), used in patients who have not responded to or who were unable to tolerate alternative MS drugs. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Clarithromycin interact?

•Drug A: Adalimumab •Drug B: Clarithromycin •Severity: MODERATE •Description: The metabolism of Clarithromycin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): An alternative medication for the treatment of acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae in patients with a history of type I penicillin hypersensitivity. Also for the treatment of pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes, as well as respiratory tract infections including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, mild to moderate community-acquired pneuomia, Legionnaires' disease, and pertussis. Other indications include treatment of uncomplicated skin or skin structure infections, helicobacter pylori infection, duodenal ulcer disease, bartonella infections, early Lyme disease, and encephalitis caused by Toxoplasma gondii (in HIV infected patients in conjunction with pyrimethamine). Clarithromycin may also decrease the incidence of cryptosporidiosis, prevent the occurence of α-hemolytic (viridans group) streptococcal endocarditis, as well as serve as a primary prevention for Mycobacterium avium complex (MAC) bacteremia or disseminated infections (in adults, adolescents, and children with advanced HIV infection). Clarithromycin is indicated in combination with vonoprazan and amoxicillin as co-packaged triple therapy to treat Helicobacter pylori ( H. pylori ) infection in adults. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clarithromycin is a macrolide antibiotic whose spectrum of activity includes many gram-positive ( Staphylococcus aureus, S. pneumoniae, and S. pyogenes ) and gram-negative aerobic bacteria ( Haemophilus influenzae, H. parainfluenzae, and Moraxella catarrhalis ), many anaerobic bacteria, some mycobacteria, and some other organisms including Mycoplasma, Ureaplasma, Chlamydia, Toxoplasma, and Borrelia. Other aerobic bacteria that clarithromycin has activity against include C. pneumoniae and M. pneumoniae. Clarithromycin has an in-vitro activity that is similar or greater than that of erythromycin against erythromycin-susceptible organisms. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and the drug concentration. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Clarithromycin is well-absorbed, acid stable and may be taken with food. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~ 70% protein bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic - predominantly metabolized by CYP3A4 resulting in numerous drug interactions. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 3-4 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of toxicity include diarrhea, nausea, abnormal taste, dyspepsia, and abdominal discomfort. Transient hearing loss with high doses has been observed. Pseudomembraneous colitis has been reported with clarithromycin use. Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have also occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic failure is usually reversible, but fatalities have been reported. Clarithromycin may also cause tooth decolouration which may be removed by dental cleaning. Fetal abnormalities, such as cardiovascular defects, cleft palate and fetal growth retardation, have been observed in animals. Clarithromycin may cause QT prolongation. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Biaxin, Biaxin Bid, Omeclamox, Prevpac, Voquezna 14 Day Triplepak 20;500;500 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-O-methyl erythromycin 6-O-methylerythromycin 6-O-methylerythromycin A Clarithromycin Clarithromycina Clarithromycine Clarithromycinum Claritromicina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clarithromycin is a macrolide antibiotic used for the treatment of a wide variety of bacterial infections such as acute otitis, pharyngitis, tonsillitis, respiratory tract infections, uncomplicated skin infections, and helicobacter pylori infection.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clarithromycin interact? Information: •Drug A: Adalimumab •Drug B: Clarithromycin •Severity: MODERATE •Description: The metabolism of Clarithromycin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): An alternative medication for the treatment of acute otitis media caused by H. influenzae, M. catarrhalis, or S. pneumoniae in patients with a history of type I penicillin hypersensitivity. Also for the treatment of pharyngitis and tonsillitis caused by susceptible Streptococcus pyogenes, as well as respiratory tract infections including acute maxillary sinusitis, acute bacterial exacerbations of chronic bronchitis, mild to moderate community-acquired pneuomia, Legionnaires' disease, and pertussis. Other indications include treatment of uncomplicated skin or skin structure infections, helicobacter pylori infection, duodenal ulcer disease, bartonella infections, early Lyme disease, and encephalitis caused by Toxoplasma gondii (in HIV infected patients in conjunction with pyrimethamine). Clarithromycin may also decrease the incidence of cryptosporidiosis, prevent the occurence of α-hemolytic (viridans group) streptococcal endocarditis, as well as serve as a primary prevention for Mycobacterium avium complex (MAC) bacteremia or disseminated infections (in adults, adolescents, and children with advanced HIV infection). Clarithromycin is indicated in combination with vonoprazan and amoxicillin as co-packaged triple therapy to treat Helicobacter pylori ( H. pylori ) infection in adults. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clarithromycin is a macrolide antibiotic whose spectrum of activity includes many gram-positive ( Staphylococcus aureus, S. pneumoniae, and S. pyogenes ) and gram-negative aerobic bacteria ( Haemophilus influenzae, H. parainfluenzae, and Moraxella catarrhalis ), many anaerobic bacteria, some mycobacteria, and some other organisms including Mycoplasma, Ureaplasma, Chlamydia, Toxoplasma, and Borrelia. Other aerobic bacteria that clarithromycin has activity against include C. pneumoniae and M. pneumoniae. Clarithromycin has an in-vitro activity that is similar or greater than that of erythromycin against erythromycin-susceptible organisms. Clarithromycin is usually bacteriostatic, but may be bactericidal depending on the organism and the drug concentration. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clarithromycin is first metabolized to 14-OH clarithromycin, which is active and works synergistically with its parent compound. Like other macrolides, it then penetrates bacteria cell wall and reversibly binds to domain V of the 23S ribosomal RNA of the 50S subunit of the bacterial ribosome, blocking translocation of aminoacyl transfer-RNA and polypeptide synthesis. Clarithromycin also inhibits the hepatic microsomal CYP3A4 isoenzyme and P-glycoprotein, an energy-dependent drug efflux pump. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Clarithromycin is well-absorbed, acid stable and may be taken with food. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~ 70% protein bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic - predominantly metabolized by CYP3A4 resulting in numerous drug interactions. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After a 250 mg tablet every 12 hours, approximately 20% of the dose is excreted in the urine as clarithromycin, while after a 500 mg tablet every 12 hours, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 3-4 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Symptoms of toxicity include diarrhea, nausea, abnormal taste, dyspepsia, and abdominal discomfort. Transient hearing loss with high doses has been observed. Pseudomembraneous colitis has been reported with clarithromycin use. Allergic reactions ranging from urticaria and mild skin eruptions to rare cases of anaphylaxis and Stevens-Johnson syndrome have also occurred. Rare cases of severe hepatic dysfunctions also have been reported. Hepatic failure is usually reversible, but fatalities have been reported. Clarithromycin may also cause tooth decolouration which may be removed by dental cleaning. Fetal abnormalities, such as cardiovascular defects, cleft palate and fetal growth retardation, have been observed in animals. Clarithromycin may cause QT prolongation. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Biaxin, Biaxin Bid, Omeclamox, Prevpac, Voquezna 14 Day Triplepak 20;500;500 •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 6-O-methyl erythromycin 6-O-methylerythromycin 6-O-methylerythromycin A Clarithromycin Clarithromycina Clarithromycine Clarithromycinum Claritromicina •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clarithromycin is a macrolide antibiotic used for the treatment of a wide variety of bacterial infections such as acute otitis, pharyngitis, tonsillitis, respiratory tract infections, uncomplicated skin infections, and helicobacter pylori infection. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Adalimumab and Clevidipine interact?

•Drug A: Adalimumab •Drug B: Clevidipine •Severity: MODERATE •Description: The metabolism of Clevidipine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the reduction of blood pressure when when oral antihypertensive therapy is not feasible or not desirable. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >99.5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): urine 63-74%, feces 7-22% •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 1 minute •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cleviprex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clevidipine is a dihydropyridine L-type calcium channel blocker used to lower blood pressure when oral antihypertensive therapy is not feasible or not desirable.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clevidipine interact? Information: •Drug A: Adalimumab •Drug B: Clevidipine •Severity: MODERATE •Description: The metabolism of Clevidipine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the reduction of blood pressure when when oral antihypertensive therapy is not feasible or not desirable. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clevidipine belongs to a well-known class of drugs called dihydropyridine calcium channel antagonists. Clevidpine is the first third generation intravenous dihydropyridine calcium channel blocker. In vitro studies demonstrated that clevidipine acts by selectively relaxing the smooth muscle cells that line small arteries, resulting in arterial dilation, widening of the artery opening, and without reducing central venous pressure or reducing cardiac output. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Possibly by deforming the channel, inhibiting ion-control gating mechanisms, and/or interfering with the release of calcium from the sarcoplasmic reticulum, clevidipine inhibits the influx of extracellular calcium across both the myocardial and vascular smooth muscle cell membranes. The resultant inhibition of the contractile processes of the myocardial smooth muscle cells leads to dilation of the coronary and systemic arteries and improved oxygen delivery to the myocardial tissue. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): >99.5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clevidipine is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): urine 63-74%, feces 7-22% •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 1 minute •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cleviprex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clevidipine is a dihydropyridine L-type calcium channel blocker used to lower blood pressure when oral antihypertensive therapy is not feasible or not desirable. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Clindamycin interact?

•Drug A: Adalimumab •Drug B: Clindamycin •Severity: MODERATE •Description: The metabolism of Clindamycin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): In oral and parenteral formulations, clindamycin is indicated for the treatment of serious infections caused by susceptible anaerobic bacteria, as well as susceptible staphylococci, streptococci, and pneumococci. Used topically, it is indicated for the treatment of acne vulgaris and is available in combination with benzoyl peroxide or tretinoin for this purpose, or as a triple combination therapy with benzoyl peroxide and adapalene. Clindamycin is also indicated as a vaginal cream, suppository, or gel for the treatment of bacterial vaginosis in non-pregnant females. Clindamycin is used for antimicrobial prophylaxis against Viridans group streptococcal infections in susceptible patients undergoing oral, dental, or upper respiratory surgery, and may be used for prophylaxis against bacterial endocarditis in penicillin-allergic patients at high risk of these infections. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clindamycin exerts its bacteriostatic effect via inhibition of microbial protein synthesis. Clindamycin has a relatively short T max and half-life necessitating administration every six hours to ensure adequate antibiotic concentrations. Clostridium difficile associated diarrhea (CDAD) has been observed in patients using clindamycin, ranging in severity from mild diarrhea to fatal colitis and occasionally occurring over two months following cessation of antibiotic therapy. Overgrowth of C. difficile resulting from antibiotic use, along with its production of A and B toxins, contributes to morbidity and mortality in these patients. Because of the associated risks, clindamycin should be reserved for serious infections for which the use of less toxic antimicrobial agents are inappropriate. Clindamycin is active against a number of gram-positive aerobic bacteria, as well as both gram-positive and gram-negative anaerobes. Resistance to clindamycin may develop, and is generally the result of base modification within the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete, and may also occur between clindamycin and macrolide antibiotics (e.g. erythromycin ) due to similarities in their binding sites. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clindamycin inhibits bacterial protein synthesis by binding to 23S RNA of the 50S subunit of the bacterial ribosome. It impedes both the assembly of the ribosome and the translation process. The molecular mechanism through which this occurs is thought to be due to clindamycin's three-dimensional structure, which closely resembles the 3'-ends of L-Pro-Met-tRNA and deacylated-tRNA during the peptide elongation cycle - in acting as a structural analog of these tRNA molecules, clindamycin impairs peptide chain initiation and may stimulate dissociation of peptidyl-tRNA from bacterial ribosomes. The mechanism through which topical clindamycin treats acne vulgaris is unclear, but may be related to its activity against Propionibacterium acnes, a bacteria that has been associated with acne. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Oral bioavailability is nearly complete, at approximately 90%, and peak serum concentrations (C max ) of, on average, 2.50 µg/mL are reached at 0.75 hours (T max ). The AUC following an orally administered dose of 300mg was found to be approximately 11 µg•hr/mL. Systemic exposure from the administration of vaginal suppository formulations is 40-fold to 50-fold lower than that observed following parenteral administration and the C max observed following administration of vaginal cream formulations was 0.1% of that observed following parenteral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Clindamycin is widely distributed in the body, including into bone, but does not distribute into cerebrospinal fluid. The volume of distribution has been variably estimated between 43-74 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clindamycin protein binding is concentration-dependent and ranges from 60-94%. It is bound primarily to alpha-1-acid glycoprotein in the serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clindamycin undergoes hepatic metabolism mediated primarily by CYP3A4 and, to a lesser extent, CYP3A5. Two inactive metabolites have been identified - an oxidative metabolite, clindamycin sulfoxide, and an N-demethylated metabolite, N-desmethylclindamycin. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 10% of clindamycin bioactivity is excreted in the urine and 3.6% in the feces, with the remainder excreted as inactive metabolites. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life of clindamycin is about 3 hours in adults and 2.5 hours in children. Half-life is increased to approximately 4 hours in the elderly. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The plasma clearance of clindamycin is estimated to be 12.3-17.4 L/h, and is reduced in patients with cirrhosis and altered in those with anemia. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 in mice and rats is 2540 mg/kg and 2190 mg/kg, respectively. While no cases of overdose have been reported, symptoms are expected to be consistent with the adverse effect profile of clindamycin and may therefore include abdominal pain, nausea, vomiting, and diarrhea. During clinical trials, one 3-year-old child was given a dose of 100 mg/kg daily for 5 days and showed only mild abdominal pain and diarrhea. Activated charcoal may be of value to remove unabsorbed drug, but hemodialysis and peritoneal dialysis are ineffective. General supportive measures are recommended in cases of clindamycin overdose. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Acanya, Benzaclin, Biacna, Cabtreo, Cleocin, Cleocin-T, Clindacin, Clindagel, Clindesse, Clindoxyl, Dalacin, Dalacin C, Duac, Evoclin, Neuac, Onexton, Veltin, Xaciato, Ziana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 7-CDL Clindamicina Clindamycin Clindamycine Clindamycinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clindamycin is a lincosamide antibiotic used to treat serious infections caused by susceptible anaerobic, streptococcal, staphylococcal, and pneumococcal bacteria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clindamycin interact? Information: •Drug A: Adalimumab •Drug B: Clindamycin •Severity: MODERATE •Description: The metabolism of Clindamycin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): In oral and parenteral formulations, clindamycin is indicated for the treatment of serious infections caused by susceptible anaerobic bacteria, as well as susceptible staphylococci, streptococci, and pneumococci. Used topically, it is indicated for the treatment of acne vulgaris and is available in combination with benzoyl peroxide or tretinoin for this purpose, or as a triple combination therapy with benzoyl peroxide and adapalene. Clindamycin is also indicated as a vaginal cream, suppository, or gel for the treatment of bacterial vaginosis in non-pregnant females. Clindamycin is used for antimicrobial prophylaxis against Viridans group streptococcal infections in susceptible patients undergoing oral, dental, or upper respiratory surgery, and may be used for prophylaxis against bacterial endocarditis in penicillin-allergic patients at high risk of these infections. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clindamycin exerts its bacteriostatic effect via inhibition of microbial protein synthesis. Clindamycin has a relatively short T max and half-life necessitating administration every six hours to ensure adequate antibiotic concentrations. Clostridium difficile associated diarrhea (CDAD) has been observed in patients using clindamycin, ranging in severity from mild diarrhea to fatal colitis and occasionally occurring over two months following cessation of antibiotic therapy. Overgrowth of C. difficile resulting from antibiotic use, along with its production of A and B toxins, contributes to morbidity and mortality in these patients. Because of the associated risks, clindamycin should be reserved for serious infections for which the use of less toxic antimicrobial agents are inappropriate. Clindamycin is active against a number of gram-positive aerobic bacteria, as well as both gram-positive and gram-negative anaerobes. Resistance to clindamycin may develop, and is generally the result of base modification within the 23S ribosomal RNA. Cross-resistance between clindamycin and lincomycin is complete, and may also occur between clindamycin and macrolide antibiotics (e.g. erythromycin ) due to similarities in their binding sites. As antimicrobial susceptibility patterns are geographically distinct, local antibiograms should be consulted to ensure adequate coverage of relevant pathogens prior to use. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clindamycin inhibits bacterial protein synthesis by binding to 23S RNA of the 50S subunit of the bacterial ribosome. It impedes both the assembly of the ribosome and the translation process. The molecular mechanism through which this occurs is thought to be due to clindamycin's three-dimensional structure, which closely resembles the 3'-ends of L-Pro-Met-tRNA and deacylated-tRNA during the peptide elongation cycle - in acting as a structural analog of these tRNA molecules, clindamycin impairs peptide chain initiation and may stimulate dissociation of peptidyl-tRNA from bacterial ribosomes. The mechanism through which topical clindamycin treats acne vulgaris is unclear, but may be related to its activity against Propionibacterium acnes, a bacteria that has been associated with acne. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Oral bioavailability is nearly complete, at approximately 90%, and peak serum concentrations (C max ) of, on average, 2.50 µg/mL are reached at 0.75 hours (T max ). The AUC following an orally administered dose of 300mg was found to be approximately 11 µg•hr/mL. Systemic exposure from the administration of vaginal suppository formulations is 40-fold to 50-fold lower than that observed following parenteral administration and the C max observed following administration of vaginal cream formulations was 0.1% of that observed following parenteral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Clindamycin is widely distributed in the body, including into bone, but does not distribute into cerebrospinal fluid. The volume of distribution has been variably estimated between 43-74 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clindamycin protein binding is concentration-dependent and ranges from 60-94%. It is bound primarily to alpha-1-acid glycoprotein in the serum. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clindamycin undergoes hepatic metabolism mediated primarily by CYP3A4 and, to a lesser extent, CYP3A5. Two inactive metabolites have been identified - an oxidative metabolite, clindamycin sulfoxide, and an N-demethylated metabolite, N-desmethylclindamycin. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 10% of clindamycin bioactivity is excreted in the urine and 3.6% in the feces, with the remainder excreted as inactive metabolites. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life of clindamycin is about 3 hours in adults and 2.5 hours in children. Half-life is increased to approximately 4 hours in the elderly. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The plasma clearance of clindamycin is estimated to be 12.3-17.4 L/h, and is reduced in patients with cirrhosis and altered in those with anemia. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 in mice and rats is 2540 mg/kg and 2190 mg/kg, respectively. While no cases of overdose have been reported, symptoms are expected to be consistent with the adverse effect profile of clindamycin and may therefore include abdominal pain, nausea, vomiting, and diarrhea. During clinical trials, one 3-year-old child was given a dose of 100 mg/kg daily for 5 days and showed only mild abdominal pain and diarrhea. Activated charcoal may be of value to remove unabsorbed drug, but hemodialysis and peritoneal dialysis are ineffective. General supportive measures are recommended in cases of clindamycin overdose. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Acanya, Benzaclin, Biacna, Cabtreo, Cleocin, Cleocin-T, Clindacin, Clindagel, Clindesse, Clindoxyl, Dalacin, Dalacin C, Duac, Evoclin, Neuac, Onexton, Veltin, Xaciato, Ziana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 7-CDL Clindamicina Clindamycin Clindamycine Clindamycinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clindamycin is a lincosamide antibiotic used to treat serious infections caused by susceptible anaerobic, streptococcal, staphylococcal, and pneumococcal bacteria. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Adalimumab and Clobazam interact?

•Drug A: Adalimumab •Drug B: Clobazam •Severity: MODERATE •Description: The metabolism of Clobazam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clobazam belongs to the benzodiazepine class of drugs. Clobazam acts on the GABA A receptor to increase GABAnergic transmission, particularly chloride conductance in neurons. This causes neuronal hyperpolarization, resulting in an increase in the action potential threshold and reducing neuron firing frequency. Consequently, the general neuronal activity of the central nervous system is depressed; therefore, clobazam can be used to treat diseases caused by excessive excitatory action potentials. The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve the potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA A receptor. Specifically, clobazam binds to the interface of the α 2 and γ 2 -subunit of the GABA A receptor. It has a great affinity for the α 2 subunit than the α 1 subunit compared to other 1,4‐benzodiazepines. Binding of clobazam to the GABA A receptor causes chloride channels to open, resulting in an influx of chloride and thus hyperpolarization of neurons. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of ONFI. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day. Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (T max ) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single-dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours. Based on exposure (C max and AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation to form two major metabolites, N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, respectively, with approximately 2% of the dose recovered in urine and 1% in feces as an unchanged drug. The N-demethylation reaction is catalyzed primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to the parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively hydroxylated, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine.. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19. The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): After a 20 to 40 mg/day administration of clobazam, the oral clearance is calculated to be 1.9 to 2.3 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association between benzodiazepines and major birth defects. Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. ONFI should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise a pregnant woman and women of childbearing age of the potential risk to a fetus. Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to clobazam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to clobazam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8)]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)]. In a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when the drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients. In mice, oral administration of clobazam (0, 6, 12, or 24 mg/kg/day) for 2 years did not result in an increase in tumors. The highest dose tested was approximately 3 times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m2). In rats, oral administration of clobazam for 2 years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses. The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD. Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays. In a fertility study in which clobazam (50, 350, or 750 mg/kg/day, corresponding to 12, 84, and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40 mg/day based on mg/m2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no-effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day. Clobazam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)]. The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam. Clobazam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. In clinical trials, cases of dependency were reported following the abrupt discontinuation of clobazam. Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g.,nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis,hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance to clobazam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of clobazam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raises the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Onfi, Sympazan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Clobazam Clobazamum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clobazam is a benzodiazepine used as adjunct treatment in seizures associated with Lennox-Gastaut syndrome.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clobazam interact? Information: •Drug A: Adalimumab •Drug B: Clobazam •Severity: MODERATE •Description: The metabolism of Clobazam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clobazam is indicated for the adjunctive treatment of seizures associated with Lennox-Gastaut syndrome (LGS) in patients 2 years of age or older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clobazam belongs to the benzodiazepine class of drugs. Clobazam acts on the GABA A receptor to increase GABAnergic transmission, particularly chloride conductance in neurons. This causes neuronal hyperpolarization, resulting in an increase in the action potential threshold and reducing neuron firing frequency. Consequently, the general neuronal activity of the central nervous system is depressed; therefore, clobazam can be used to treat diseases caused by excessive excitatory action potentials. The effect of clobazam 20 mg and 80 mg administered twice daily on QTc interval was evaluated in a randomized, evaluator-blinded, placebo-, and active-controlled (moxifloxacin 400 mg) parallel thorough QT study in 280 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo-adjusted, baseline-corrected QTc based on the Fridericia correction method was below 10 ms, the threshold for regulatory concern. Thus, at a dose two times the maximum recommended dose, clobazam did not prolong the QTc interval to any clinically relevant extent. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of action for clobazam, a 1,5-benzodiazepine, is not fully understood but is thought to involve the potentiation of GABAergic neurotransmission resulting from binding at the benzodiazepine site of the GABA A receptor. Specifically, clobazam binds to the interface of the α 2 and γ 2 -subunit of the GABA A receptor. It has a great affinity for the α 2 subunit than the α 1 subunit compared to other 1,4‐benzodiazepines. Binding of clobazam to the GABA A receptor causes chloride channels to open, resulting in an influx of chloride and thus hyperpolarization of neurons. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The peak plasma levels (Cmax) and the area under the curve (AUC) of clobazam are dose-proportional over the dose range of 10-80 mg following single- or multiple-dose administration of ONFI. Based on a population pharmacokinetic analysis, the pharmacokinetics of clobazam are linear from 5-160 mg/day. Clobazam is rapidly and extensively absorbed following oral administration. The time to peak concentrations (T max ) of clobazam tablets under fasted conditions ranged from 0.5 to 4 hours after single- or multiple-dose administrations. The relative bioavailability of clobazam tablets compared to an oral solution is approximately 100%. After single-dose administration of the oral suspension under fasted conditions, the Tmax ranged from 0.5 to 2 hours. Based on exposure (C max and AUC) of clobazam, clobazam tablets and suspension were shown to have similar bioavailability under fasted conditions. The administration of clobazam tablets with food or when crushed in applesauce does not affect absorption. Although not studied, the oral bioavailability of the oral suspension is unlikely to be affected under fed conditions. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Clobazam is lipophilic and distributes rapidly throughout the body. The apparent volume of distribution at steady state was approximately 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The in vitro plasma protein binding of clobazam and N-desmethylclobazam is approximately 80-90% and 70%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clobazam is extensively metabolized in the liver via N-demethylation and hydroxylation to form two major metabolites, N-desmethylclobazam (norclobazam) and 4'-hydroxyclobazam, respectively, with approximately 2% of the dose recovered in urine and 1% in feces as an unchanged drug. The N-demethylation reaction is catalyzed primarily by CYP3A4 and to a lesser extent by CYP2C19 and CYP2B6. N-desmethylclobazam, an active metabolite, is the major circulating metabolite in humans, and at therapeutic doses, plasma concentrations are 3-5 times higher than those of the parent compound. Based on animal and in vitro receptor binding data, estimates of the relative potency of N-desmethylclobazam compared to the parent compound range from 1/5 to equal potency. N-desmethylclobazam is extensively hydroxylated, mainly by CYP2C19. N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine.. The formation of 4'-hydroxyclobazam is facilitated by CYP2C18 and CYP2C19. The polymorphic CYP2C19 is the major contributor to the metabolism of the pharmacologically active N-desmethylclobazam. In CYP2C19 poor metabolizers, levels of N-desmethylclobazam were 5-fold higher in plasma and 2- to 3-fold higher in the urine than in CYP2C19 extensive metabolizers. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): N-desmethylclobazam and its metabolites comprise ~94% of the total drug-related components in urine. Following a single oral dose of radiolabeled drug, approximately 11% of the dose was excreted in the feces and approximately 82% was excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The estimated mean elimination half-lives (t½) of clobazam and N-desmethylclobazam were 36-42 hours and 71-82 hours, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): After a 20 to 40 mg/day administration of clobazam, the oral clearance is calculated to be 1.9 to 2.3 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.8) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association between benzodiazepines and major birth defects. Administration of clobazam to pregnant rats and rabbits during the period of organogenesis or to rats throughout pregnancy and lactation resulted in developmental toxicity, including increased incidences of fetal malformations and mortality, at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those expected at therapeutic doses in patients. Data for other benzodiazepines suggest the possibility of long-term effects on neurobehavioral and immunological function in animals following prenatal exposure to benzodiazepines at clinically relevant doses. ONFI should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Advise a pregnant woman and women of childbearing age of the potential risk to a fetus. Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to clobazam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to clobazam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.8)]. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Administration of clobazam to rats prior to and during mating and early gestation resulted in adverse effects on fertility and early embryonic development at plasma exposures for clobazam and its major active metabolite, N-desmethylclobazam, below those in humans at the MRHD [see Nonclinical Toxicology (13.1)]. In a study in which clobazam (0, 4, 36, or 120 mg/kg/day) was orally administered to rats during the juvenile period of development (postnatal days 14 to 48), adverse effects on growth (decreased bone density and bone length) and behavior (altered motor activity and auditory startle response; learning deficit) were observed at the high dose. The effect on bone density, but not on behavior, was reversible when the drug was discontinued. The no-effect level for juvenile toxicity (36 mg/kg/day) was associated with plasma exposures (AUC) to clobazam and its major active metabolite, N-desmethylclobazam, less than those expected at therapeutic doses in pediatric patients. In mice, oral administration of clobazam (0, 6, 12, or 24 mg/kg/day) for 2 years did not result in an increase in tumors. The highest dose tested was approximately 3 times the maximum recommended human dose (MRHD) of 40 mg/day, based on body surface area (mg/m2). In rats, oral administration of clobazam for 2 years resulted in increases in tumors of the thyroid gland (follicular cell adenoma and carcinoma) and liver (hepatocellular adenoma) at the mid and high doses. The low dose, not associated with an increase in tumors, was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than that in humans at the MRHD. Clobazam and the major active metabolite, N-desmethylclobazam, were negative for genotoxicity, based on data from a battery of in vitro (bacteria reverse mutation, mammalian clastogenicity) and in vivo (mouse micronucleus) assays. In a fertility study in which clobazam (50, 350, or 750 mg/kg/day, corresponding to 12, 84, and 181 times the oral Maximum Recommended Human Dose, MRHD, of 40 mg/day based on mg/m2 body surface) was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6, increases in abnormal sperm and pre-implantation loss were observed at the highest dose tested. The no-effect level for fertility and early embryonic development in rats was associated with plasma exposures (AUC) for clobazam and its major active metabolite, N-desmethylclobazam, less than those in humans at the maximum recommended human dose of 40 mg/day. Clobazam is a benzodiazepine and a CNS depressant with a potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of a drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of a drug by an individual in a way other than prescribed by a health care provider or for whom it was not prescribed. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving a higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse of benzodiazepines may lead to addiction. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)]. The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo. The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). The World Health Organization epidemiology database contains reports of drug abuse, misuse, and overdoses associated with clobazam. Clobazam may produce physical dependence from continued therapy. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, a benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. In clinical trials, cases of dependency were reported following the abrupt discontinuation of clobazam. Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g.,nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis,hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond 4 to 6 weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As a result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used. Tolerance to clobazam may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of clobazam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines. Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2)]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raises the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway maintenance. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Onfi, Sympazan •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Clobazam Clobazamum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clobazam is a benzodiazepine used as adjunct treatment in seizures associated with Lennox-Gastaut syndrome. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Clobetasol propionate interact?

•Drug A: Adalimumab •Drug B: Clobetasol propionate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Clobetasol propionate. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clobetasol propionate is indicated to treat moderate to severe plaque psoriasis as well as inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. Clobetasol propionate is generally applied twice daily so the duration of action is long. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Twice daily application of clobetasol foam leads to a C max of 59±36pg/mL with a T max of 5 hours. Clobetasol cream showed an increase in clobetasol concentrations from 50.7±96.0pg/mL to 56.3±104.7pg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Data regarding the volume of distribution of clobetasole propionate are not readily available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the protein binding of clobetasol propionate are not readily available. Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of clobetasol propionate is not well studied but it does induce metabolic enzymes, even when delivered topically. The metabolism of clobetasol propionate is predicted to follow similar metabolic pathways to other corticosteroids including the addition of oxygen, hydrogen, glucuronides, and sulfates to form water soluble metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Data regarding the half life of clobetasol propionate are not readily available. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Data regarding the clearance of clobetasol propionate are not readily available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding acute overdoses of glucocorticoids are rare. Overdoses of clobetasol propionate can lead to reversible HPA axis suppression and glucocorticoid insufficiency. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Clobex, Clodan, Dermovate, Impeklo, Impoyz, Olux, Temovate, Tovet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): clobetasol 17-propanoate clobetasol 17-propionate Clobetasol propionate Clobetasol propionate E •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clobetasol propionate is a corticosteroid used to treat corticosteroid-responsive dermatoses and plaque psoriasis.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Clobetasol propionate interact? Information: •Drug A: Adalimumab •Drug B: Clobetasol propionate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Clobetasol propionate. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clobetasol propionate is indicated to treat moderate to severe plaque psoriasis as well as inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. Clobetasol propionate is generally applied twice daily so the duration of action is long. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Twice daily application of clobetasol foam leads to a C max of 59±36pg/mL with a T max of 5 hours. Clobetasol cream showed an increase in clobetasol concentrations from 50.7±96.0pg/mL to 56.3±104.7pg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Data regarding the volume of distribution of clobetasole propionate are not readily available. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the protein binding of clobetasol propionate are not readily available. Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of clobetasol propionate is not well studied but it does induce metabolic enzymes, even when delivered topically. The metabolism of clobetasol propionate is predicted to follow similar metabolic pathways to other corticosteroids including the addition of oxygen, hydrogen, glucuronides, and sulfates to form water soluble metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Data regarding the half life of clobetasol propionate are not readily available. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Data regarding the clearance of clobetasol propionate are not readily available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding acute overdoses of glucocorticoids are rare. Overdoses of clobetasol propionate can lead to reversible HPA axis suppression and glucocorticoid insufficiency. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Clobex, Clodan, Dermovate, Impeklo, Impoyz, Olux, Temovate, Tovet •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): clobetasol 17-propanoate clobetasol 17-propionate Clobetasol propionate Clobetasol propionate E •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clobetasol propionate is a corticosteroid used to treat corticosteroid-responsive dermatoses and plaque psoriasis. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Clofarabine interact?

•Drug A: Adalimumab •Drug B: Clofarabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Clofarabine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 172 L/m2 •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 47% bound to plasma proteins, predominantly to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life is estimated to be 5.2 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 28.8 L/h/m2 [Pediatric patients (2 - 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m basis) has been 70 mg/m /day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Clolar, Evoltra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): CAFdA Clofarabin Clofarabina Clofarabine Clofarabinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clofarabine is a purine nucleoside used to treat relapsed or refractory acute lymphoblastic leukemia in patients 1 to 21 years old.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Clofarabine interact? Information: •Drug A: Adalimumab •Drug B: Clofarabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Clofarabine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphocytic (lymphoblastic) leukemia after at least two prior regimens. It is designated as an orphan drug by the FDA for this use. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clofarabine is a purine nucleoside antimetabolite that differs from other puring nucleoside analogs by the presence of a chlorine in the purine ring and a flourine in the ribose moiety. Clofarabine seems to interfere with the growth of cancer cells, which are eventually destroyed. Since the growth of normal body cells may also be affected by clofarabine, other effects also occur. Clofarabine prevents cells from making DNA and RNA by interfering with the synthesis of nucleic acids, thus stopping the growth of cancer cells. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clofarabine is metabolized intracellularly to the active 5'-monophosphate metabolite by deoxycytidine kinase and 5'-triphosphate metabolite by mono- and di-phospho-kinases. This metabolite inhibits DNA synthesis through an inhibitory action on ribonucleotide reductase, and by terminating DNA chain elongation and inhibiting repair through competitive inhibition of DNA polymerases. This leads to the depletion of the intracellular deoxynucleotide triphosphate pool and the self-potentiation of clofarabine triphosphate incorporation into DNA, thereby intensifying the effectiveness of DNA synthesis inhibition. The affinity of clofarabine triphosphate for these enzymes is similar to or greater than that of deoxyadenosine triphosphate. In preclinical models, clofarabine has demonstrated the ability to inhibit DNA repair by incorporation into the DNA chain during the repair process. Clofarabine 5'-triphosphate also disrupts the integrity of mitochondrial membrane, leading to the release of the pro-apoptotic mitochondrial proteins, cytochrome C and apoptosis-inducing factor, leading to programmed cell death. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 172 L/m2 •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 47% bound to plasma proteins, predominantly to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clofarabine is sequentially metabolized intracellularly to the 5’-monophosphate metabolite by deoxycytidine kinase and mono- and di-phosphokinases to the active 5’-triphosphate metabolite. Clofarabine has high affinity for the activating phosphorylating enzyme, deoxycytidine kinase, equal to or greater than that of the natural substrate, deoxycytidine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Based on 24-hour urine collections in the pediatric studies, 49 - 60% of the dose is excreted in the urine unchanged. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life is estimated to be 5.2 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 28.8 L/h/m2 [Pediatric patients (2 - 19 years old) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) receiving 52 mg/m2 dose] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There were no known overdoses of clofarabine. The highest daily dose administered to a human to date (on a mg/m basis) has been 70 mg/m /day × 5 days (2 pediatric ALL patients). The toxicities included in these 2 patients included grade 4 hyperbilirubinemia, grade 2 and 3 vomiting, and grade 3 maculopapular rash. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Clolar, Evoltra •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): CAFdA Clofarabin Clofarabina Clofarabine Clofarabinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clofarabine is a purine nucleoside used to treat relapsed or refractory acute lymphoblastic leukemia in patients 1 to 21 years old. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Clomipramine interact?

•Drug A: Adalimumab •Drug B: Clomipramine •Severity: MAJOR •Description: The metabolism of Clomipramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Anafranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Clomipramine interact? Information: •Drug A: Adalimumab •Drug B: Clomipramine •Severity: MAJOR •Description: The metabolism of Clomipramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): May be used to treat obsessive-compulsive disorder and disorders with an obsessive-compulsive component (e.g. depression, schizophrenia, Tourette’s disorder). Unlabeled indications include: depression, panic disorder, chronic pain (e.g. central pain, idiopathic pain disorder, tension headache, diabetic peripheral neuropathy, neuropathic pain), cataplexy and associated narcolepsy (limited evidence), autistic disorder (limited evidence), trichotillomania (limited evidence), onchophagia (limited evidence), stuttering (limited evidence), premature ejaculation, and premenstrual syndrome. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clomipramine, a tricyclic antidepressant, is the 3-chloro derivative of Imipramine. It was thought that tricyclic antidepressants work exclusively by inhibiting the re-uptake of the neurotransmitters norepinephrine and serotonin by nerve cells. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. Presynaptic receptors are affected: α 1 and β 1 receptors are sensitized, α 2 receptors are desensitized (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clomipramine is a strong, but not completely selective serotonin reuptake inhibitor (SRI), as the active main metabolite desmethyclomipramine acts preferably as an inhibitor of noradrenaline reuptake. α 1 -receptor blockage and β-down-regulation have been noted and most likely play a role in the short term effects of clomipramine. A blockade of sodium-channels and NDMA-receptors might, as with other tricyclics, account for its effect in chronic pain, in particular the neuropathic type. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Well absorbed from the GI tract following oral administration. Bioavailability is approximately 50% orally due to extensive first-pass metabolism. Bioavailability is not affected by food. Peak plasma concentrations occurred 2-6 hours following oral administration of a single 50 mg dose. The peak plasma concentration ranged from 56 ng/mL to 154 mg/mL (mean, 92 ng/mL). There are large interindividual variations in plasma concentrations occur, partly due to genetic differences in clomipramine metabolism. On average, steady state plasma concentrations are achieved in 1-2 weeks following multiple dose oral administration. Smoking appears to lower the steady-state plasma concentration of clomipramine, but not its active metabolite desmethylclomipramine. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): ~ 17 L/kg (range: 9-25 L/kg). Clomipramine is capable of distributing into the cerebrospinal fluid, the brain, and into breast milk. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clomipramine is approximately 97-98% bound to plasma proteins, principally to albumin and possibly to α 1 -acid glycoprotein. Desmethylclomipramine is 97-99% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Extensively metabolized in the liver. The main active metabolite is desmethylclomipramine, which is formed by N -demethylation of clomipramine via CYP2C19, 3A4 and 1A2. Other metabolites and their glucuronide conjugates are also produced. Other metabolites of clomipramine include 8-hydroxyclomipramine formed via 8-hydroxylation, 2-hydroxyclomipramine formed via 2-hydroxylation, and clomipramine N -oxide formed by N -oxidation. Desmethylclomipramine is further metabolized to 8-hydroxydesmethylclomipramine and didesmethylclomipramine, which are formed by 8-hydroxylation and N -demethylation, respectively. 8-Hydroxyclomipramine and 8-hydroxydesmethylclomipramine are pharmacologically active; however, their clinical relevance remains unknown. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Urine (51-60%) and feces via biliary elimination (24-32%) •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following oral administration of a single 150 mg dose of clomipramine, the average elimination half-life of clomipramine was 32 hours (range: 19-37 hours) and of desmethylclomipramine was 69 hours (range: 54-77 hours). Elimination half-life may vary substantially with different doses due to saturable kinetics (i.e. metabolism). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Signs and symptoms vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the time elapsed since drug ingestion. Critical manifestations of overdose include cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic toxicity. In U.S. clinical trials, 2 deaths occurred in 12 reported cases of acute overdosage with Anafranil either alone or in combination with other drugs. One death involved a patient suspected of ingesting a dose of 7000 mg. The second death involved a patient suspected of ingesting a dose of 5750 mg. Side effects include: sedation, hypotension, blurred vision, dry mouth, constipation, urinary retention, postural hypotension, tachycardia, hypertension, ECG changes, heart failure, impaired memory and delirium, and precipitation of hypomanic or manic episodes in bipolar depression. Withdrawal symptoms include gastrointestinal disturbances, anxiety, and insomnia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Anafranil •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3-Chloroimipramine Chlorimipramine Clomipramina Clomipramine Clomipraminum Monochlorimipramine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clomipramine is a tricyclic antidepressant used in the treatment of obsessive-compulsive disorder and disorders with an obsessive-compulsive component, such as depression, schizophrenia, and Tourette’s disorder. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Clonidine interact?

•Drug A: Adalimumab •Drug B: Clonidine •Severity: MAJOR •Description: The metabolism of Clonidine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clonidine tablets and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient. An extended release tablet of clonidine is indicated for the treatment of ADHD either alone or in combination with other medications. Clonidine is also used for the diagnosis of pheochromocytoma, treatment of nicotine dependance, and opiate withdrawal. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins G o and G i. G i inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Clonidine binding to the alpha-2 adrenoceptor causes structural changes in the alpha subunit of the G-protein, reducing its affinity for GDP. Magnesium catalyzes the replacement of GDP with GTP. The alpha subunit dissociates from the other subunits and associates with an effector. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Clonidine reaches maximum concentration in 60-90 minutes after oral administration. Race and fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a C max of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of clonidine has been reported as 1.7-2.5L/kg, 2.9L/kg, or 2.1±0.4L/kg depending on the source. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clonidine is 20-40% bound to plasma proteins, especially albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of clonidine is 1.9-4.3mL/min/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral LD 50 is 126 mg/kg in rats. The TDLO is 70µg/kg in children, 126µg/kg in women, and 69µg/kg in men. Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. Dialysis is also unlikely to be beneficial. Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Catapres, Catapres-TTS, Catapres-tts-1, Duraclon, Kapvay, Nexiclon XR •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlofazoline Clonidin Clonidina Clonidine Clonidinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clonidine is an alpha-2 adrenergic agonist used to treat hypertension and severe cancer pain, among other conditions, and to treat withdrawal symptoms from various substances. It is also used to aid in the diagnosis of pheochromocytoma and to prevent migraines.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Clonidine interact? Information: •Drug A: Adalimumab •Drug B: Clonidine •Severity: MAJOR •Description: The metabolism of Clonidine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clonidine tablets and transdermal systems are indicated for the treatment of hypertension alone or in combination with other medications. A clonidine injection is indicated for use with opiates in the treatment of severe cancer pain where opiates alone are insufficient. An extended release tablet of clonidine is indicated for the treatment of ADHD either alone or in combination with other medications. Clonidine is also used for the diagnosis of pheochromocytoma, treatment of nicotine dependance, and opiate withdrawal. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clonidine functions through agonism of alpha-2 adrenoceptors which have effects such as lowering blood pressure, sedation, and hyperpolarization of nerves. It has a long duration of action as it is given twice daily and the therapeutic window is between 0.1mg and 2.4mg daily. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clonidine is primarily an alpha-2 adrenoceptor agonist which causes central hypotensive and anti-arrhythmogenic effects. The alpha-2 adrenoceptor is coupled to the G-proteins G o and G i. G i inhibits adenylyl cyclase and activates opening of a potassium channel that causes hyperpolarization. Clonidine binding to the alpha-2 adrenoceptor causes structural changes in the alpha subunit of the G-protein, reducing its affinity for GDP. Magnesium catalyzes the replacement of GDP with GTP. The alpha subunit dissociates from the other subunits and associates with an effector. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Clonidine reaches maximum concentration in 60-90 minutes after oral administration. Race and fasting status do not influence pharmacokinetics of clonidine. A 100µg oral clonidine tablet reaches a C max of 400.72pg/mL with an AUC of 5606.78h*pg/mL and a bioavailability of 55-87%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of clonidine has been reported as 1.7-2.5L/kg, 2.9L/kg, or 2.1±0.4L/kg depending on the source. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clonidine is 20-40% bound to plasma proteins, especially albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of clonidine is poorly understood. The main reaction in clonidine metabolism is the 4-hydroxylation of clonidine by CYP2D6, CYP1A2, CYP3A4, CYP1A1, and CYP3A5. Clonidine is <50% metabolized in the liver to inactive metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 50% of a clonidine dose is excreted in the urine as the unchanged drug and 20% is eliminated in the feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half life after epidural administration is 30 minutes but otherwise can range from 6-23h. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of clonidine is 1.9-4.3mL/min/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral LD 50 is 126 mg/kg in rats. The TDLO is 70µg/kg in children, 126µg/kg in women, and 69µg/kg in men. Symptoms of overdose include hypertension followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased reflexes, weakness, irritability, and miosis. Severe overdoses can cause reversible cardiac conduction defects or dysrhythmias, apnea, coma, and seizures. Induction of vomiting is not recommended due to CNS depression but gastric lavage or activated charcoal may be useful in recent ingestion. Dialysis is also unlikely to be beneficial. Overdose can be treated with supportive measures such as atropine sulfate for bradycardia, intravenous fluids or vasopressors for hypotension, vasodilators for hypertension, naloxone for respiratory depression, and blood pressure monitoring. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Catapres, Catapres-TTS, Catapres-tts-1, Duraclon, Kapvay, Nexiclon XR •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Chlofazoline Clonidin Clonidina Clonidine Clonidinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clonidine is an alpha-2 adrenergic agonist used to treat hypertension and severe cancer pain, among other conditions, and to treat withdrawal symptoms from various substances. It is also used to aid in the diagnosis of pheochromocytoma and to prevent migraines. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Clopidogrel interact?

•Drug A: Adalimumab •Drug B: Clopidogrel •Severity: MODERATE •Description: The metabolism of Clopidogrel can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clopidogrel is indicated to reduce the risk of myocardial infarction for patients with non-ST elevated acute coronary syndrome (ACS), patients with ST-elevated myocardial infarction, and in recent MI, stroke, or established peripheral arterial disease, •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. It has a long duration of action as it is taken once daily and a large therapeutic window as it is given in doses of 75-300mg daily. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clopidogrel is activated via a 2 steps reaction to an active thiol-containing metabolite. This active form is a platelet inhibitor that irreversibly binds to P2Y 12 ADP receptors on platelets. This binding prevents ADP binding to P2Y 12 receptors, activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): A 75mg oral dose of clopidogrel is 50% absorbed from the intestine. Clopidogrel can be taken with or without food. A meal decreases the AUC of the active metabolite by 57%. The active metabolite of clopidogrel reaches a maximum concentration after 30-60 minutes. Clopidogrel reached a C max of 2.04±2.0ng/mL in 1.40±1.07h. The AUC for a 300mg oral dose of clopidogrel was 45.1±16.2ng*h/mL for poor metabolizers, 65.6±19.1ng*h/mL for intermediate metabolizers, and 104.3±57.3ng*h/mL for extensive metabolizers. The C max was 31.3±13ng/mL for poor metabolizers, 43.9±14ng/mL for intermediate metabolizers, and 60.8±34.3ng/mL for extensive metabolizers. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of clopidogrel is 39,240±33,520L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Both the active and inactive metabolites of clopidogrel are 98% protein bound in plasma. Studies in cows show clopidogrel 71-85.5% bound to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): 85-90% of an oral dose undergoes first pass metabolism by carboxylesterase 1 in the liver to an inactive carboxylic acid metabolite. about 2% of clopidogrel is oxidized to 2-oxoclopidogrel. This conversion is 35.8% by CYP1A2, 19.4% by CYP2B6, and 44.9% by CYP2C19 though other studies suggest CYP3A4, CYP3A5, and CYP2C9 also contribute. 2-oxoclopidogrel is further metabolized to the active metabolite. This conversion is 32.9% by CYP2B6, 6.79% by CYP2C9, 20.6% by CYP2C19, and 39.8% by CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): An oral dose of radiolabelled clopidogrel is excreted 50% in the urine and 46% in the feces over 5 days. The remainder of clopidogrel is irreversibly bound to platelets for their lifetime, or approximately 8-11 days. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): That half life of clopidogrel is approximately 6 hours following a 75mg oral dose while the half life of the active metabolite is approximately 30 minutes. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of a 75mg oral dose was 18,960±15,890L/h and for a 300mg oral dose was 16,980±10,410L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): A single dose of clopidogrel at 1500-2000mg/kg was lethal to mice and rats while 3000mg/kg was lethal to baboons. Symptoms of overdose include vomiting, breathing difficulty, gastrointestinal hemorrhage, and prostration. Clopidogrel is irreversibly bound to platelets for their lifetime, which is approximately 11 days. Overdoses of clopidogrel can be treated with platelet transfusions to restore clotting ability. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Duoplavin, Plavix, Zyllt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Clopidogrel Clopidogrelum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clopidogrel is an antiplatelet agent used to prevent blood clots in peripheral vascular disease, coronary artery disease, and cerebrovascular disease.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clopidogrel interact? Information: •Drug A: Adalimumab •Drug B: Clopidogrel •Severity: MODERATE •Description: The metabolism of Clopidogrel can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clopidogrel is indicated to reduce the risk of myocardial infarction for patients with non-ST elevated acute coronary syndrome (ACS), patients with ST-elevated myocardial infarction, and in recent MI, stroke, or established peripheral arterial disease, •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clopidogrel is a prodrug of a platelet inhibitor used to reduce the risk of myocardial infarction and stroke. It has a long duration of action as it is taken once daily and a large therapeutic window as it is given in doses of 75-300mg daily. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clopidogrel is activated via a 2 steps reaction to an active thiol-containing metabolite. This active form is a platelet inhibitor that irreversibly binds to P2Y 12 ADP receptors on platelets. This binding prevents ADP binding to P2Y 12 receptors, activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): A 75mg oral dose of clopidogrel is 50% absorbed from the intestine. Clopidogrel can be taken with or without food. A meal decreases the AUC of the active metabolite by 57%. The active metabolite of clopidogrel reaches a maximum concentration after 30-60 minutes. Clopidogrel reached a C max of 2.04±2.0ng/mL in 1.40±1.07h. The AUC for a 300mg oral dose of clopidogrel was 45.1±16.2ng*h/mL for poor metabolizers, 65.6±19.1ng*h/mL for intermediate metabolizers, and 104.3±57.3ng*h/mL for extensive metabolizers. The C max was 31.3±13ng/mL for poor metabolizers, 43.9±14ng/mL for intermediate metabolizers, and 60.8±34.3ng/mL for extensive metabolizers. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of clopidogrel is 39,240±33,520L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Both the active and inactive metabolites of clopidogrel are 98% protein bound in plasma. Studies in cows show clopidogrel 71-85.5% bound to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): 85-90% of an oral dose undergoes first pass metabolism by carboxylesterase 1 in the liver to an inactive carboxylic acid metabolite. about 2% of clopidogrel is oxidized to 2-oxoclopidogrel. This conversion is 35.8% by CYP1A2, 19.4% by CYP2B6, and 44.9% by CYP2C19 though other studies suggest CYP3A4, CYP3A5, and CYP2C9 also contribute. 2-oxoclopidogrel is further metabolized to the active metabolite. This conversion is 32.9% by CYP2B6, 6.79% by CYP2C9, 20.6% by CYP2C19, and 39.8% by CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): An oral dose of radiolabelled clopidogrel is excreted 50% in the urine and 46% in the feces over 5 days. The remainder of clopidogrel is irreversibly bound to platelets for their lifetime, or approximately 8-11 days. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): That half life of clopidogrel is approximately 6 hours following a 75mg oral dose while the half life of the active metabolite is approximately 30 minutes. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of a 75mg oral dose was 18,960±15,890L/h and for a 300mg oral dose was 16,980±10,410L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): A single dose of clopidogrel at 1500-2000mg/kg was lethal to mice and rats while 3000mg/kg was lethal to baboons. Symptoms of overdose include vomiting, breathing difficulty, gastrointestinal hemorrhage, and prostration. Clopidogrel is irreversibly bound to platelets for their lifetime, which is approximately 11 days. Overdoses of clopidogrel can be treated with platelet transfusions to restore clotting ability. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Duoplavin, Plavix, Zyllt •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Clopidogrel Clopidogrelum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clopidogrel is an antiplatelet agent used to prevent blood clots in peripheral vascular disease, coronary artery disease, and cerebrovascular disease. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Clostridium tetani toxoid antigen (formaldehyde inactivated) interact?

•Drug A: Adalimumab •Drug B: Clostridium tetani toxoid antigen (formaldehyde inactivated) •Severity: MODERATE •Description: The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Adalimumab. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Summary not found

Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Question: Does Adalimumab and Clostridium tetani toxoid antigen (formaldehyde inactivated) interact? Information: •Drug A: Adalimumab •Drug B: Clostridium tetani toxoid antigen (formaldehyde inactivated) •Severity: MODERATE •Description: The therapeutic efficacy of Clostridium tetani toxoid antigen (formaldehyde inactivated) can be decreased when used in combination with Adalimumab. •Extended Description: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Protein binding (Drug A): No protein binding available •Metabolism (Drug A): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Synonyms (Drug A): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Summary not found Output: Vaccine efficacy may be reduced when immunosuppressant medications are coadministered. Vaccines are designed to elicit an immune response, and this response may be inhibited by immunosuppressants. The administration of live vaccines can also provide a risk as the infection process can be developed due to the immunosuppressive agent. The severity of the interaction is moderate.

Does Adalimumab and Clotiazepam interact?

•Drug A: Adalimumab •Drug B: Clotiazepam •Severity: MODERATE •Description: The metabolism of Clotiazepam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of anxiety disorders. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clotiazepam is a thienodiazepine possessing anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It increases the stage 2 non-rapid eye movement sleep. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clotiazepam acts at the benzodiazepine receptors (BZD). This agonizes the action of GABA, increasing the frequency of opening of the channel chlorinates and penetration of the ions chlorinates through the ionophore. Increase in membrane polarization decreases the probability of discharge of neurons. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 4 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clotiazepam is a thienodiazepine used to manage anxiety disorders and insomnia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clotiazepam interact? Information: •Drug A: Adalimumab •Drug B: Clotiazepam •Severity: MODERATE •Description: The metabolism of Clotiazepam can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of anxiety disorders. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clotiazepam is a thienodiazepine possessing anxiolytic, anticonvulsant, sedative and skeletal muscle relaxant properties. It increases the stage 2 non-rapid eye movement sleep. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Clotiazepam acts at the benzodiazepine receptors (BZD). This agonizes the action of GABA, increasing the frequency of opening of the channel chlorinates and penetration of the ions chlorinates through the ionophore. Increase in membrane polarization decreases the probability of discharge of neurons. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 4 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clotiazepam is a thienodiazepine used to manage anxiety disorders and insomnia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2B6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Clozapine interact?

•Drug A: Adalimumab •Drug B: Clozapine •Severity: MODERATE •Description: The metabolism of Clozapine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM). Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Clozaril, Fazaclo, Versacloz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Clozapine interact? Information: •Drug A: Adalimumab •Drug B: Clozapine •Severity: MODERATE •Description: The metabolism of Clozapine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Clozapine is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, Clozapine should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. Clozapine is also indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. Suicidal behavior refers to actions by a patient that put him/herself at risk for death. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Clozapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives that is universally regarded as the treatment of choice for treatment-resistant schizophrenia. Although it is thought to mediate its pharmacological effect through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors, research have shown that clozapine can act on various types of receptors. Patients should be counseled regarding the risk of hypersensitivity reactions such as agranulocytosis and myocarditis with clozapine use. Clozapine-induced agranulocytosis, which is a reduction in the absolute neutrophil count or white blood cell count, places the patient at an increased risk for infection. Agranulocytosis is most likely to occur in the first 3-6 months of therapy, but it can still occur after years of treatment. The mechanism is thought to be a dose-independent and immune-mediated reaction against neutrophils. Patients are strictly monitored by lab testing (complete blood count with differential) to ensure agranulocytosis is detected and treated if it occurs. Testing is initially completed at one-week intervals but is expanded to two-week intervals at six months, and then four-week intervals at twelve months if lab results have been within an appropriate range. Monitoring parameters may change if there is any break in therapy. In Canada, the patient's lab values are reported to the manufacturer for hematological monitoring, and in the USA, the patient's lab values are reported to the REMS (Risk Evaluation and Mitigation Strategy) program. These programs function to notify the care provider of any significant drop in WBC/neutrophil count, or if there is a drop below a threshold level. Patients who enter the "Red" zone (WBC<2x109/L or ANC<1.5x109/L) should normally not be re-challenged. Clozapine-induced myocarditis is a hypersensitivity reaction that usually occurs in the third week of clozapine therapy and about 2% of clozapine patients. Monitor the patient's troponin, CRP, and ECG at baseline, and 28 days into treatment. Follow guidelines for appropriate next steps according to the patient's lab results. If myocarditis occurs, the patient should not be re-challenged with clozapine. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. Clozapine also acts as an antagonist at adrenergic, cholinergic, histaminergic, and other dopaminergic and serotonergic receptors. Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM). Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT 2 with similar receptor affinities may explain some of the other therapeutic and side effects of clozapine. Clozapine's antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine's antagonism of histamine H1 receptors may explain the somnolence observed with this drug. Clozapine's antagonism of adrenergic α1 receptors may explain the orthostatic hypotension observed with this drug. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In humans, clozapine tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of clozapine 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The median volume of distribution of clozapine was calculated to be 508 L (272–1290 L). •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly protein-bound drugs has not been fully evaluated but may be important. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4.The unmethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces. Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving a steady state with 100 mg twice daily dosing. A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The median clearance of clozapine is calculated to be 30.3 L/h (14.4–45.2 L/h). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): There are no adequate or well-controlled studies of clozapine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 0.4 and 0.9 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on a mg/m2 body surface area basis. The studies revealed no evidence of impaired fertility or harm to the fetus due to clozapine. Because animal reproduction studies are not always predictive of human response, CLOZARIL should be used during pregnancy only if clearly needed. Consider the risk of exacerbation of psychosis when discontinuing or changing treatment with antipsychotic medications during pregnancy and postpartum. Consider early screening for gestational diabetes for patients treated with antipsychotic medications [see Warnings and Precautions (5.11)]. Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Monitor neonates for symptoms of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding difficulties. The severity of complications can vary from self-limited symptoms to some neonates requiring intensive care unit support and prolonged hospitalization. The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g. There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. No carcinogenic potential was demonstrated in long-term studies in mice and rats at doses up to 0.3 times and 0.4 times, respectively, the maximum recommended human dose (MRHD) of 900 mg/day on an mg/m2 body surface area basis. Clozapine was not genotoxic when tested in the following gene mutation and chromosomal aberration tests: the bacterial Ames test, the in vitro mammalian V79 in Chinese hamster cells, the in vitro unscheduled DNA synthesis in rat hepatocytes or the in vivo micronucleus assay in mice. Clozapine had no effect on any parameters of fertility, pregnancy, fetal weight, or postnatal development when administered orally to male rats 70 days before mating and to female rats for 14 days before mating at doses up to 0.4 times the MRHD of 900 mg/day on an mg/m2 body surface area basis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Clozaril, Fazaclo, Versacloz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Clozapine is an atypical or second-generation antipsychotic drug used in treatment-resistant schizophrenia and to decrease suicide risk in schizophrenic patients. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cobicistat interact?

•Drug A: Adalimumab •Drug B: Cobicistat •Severity: MODERATE •Description: The metabolism of Cobicistat can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection. It is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of cobicistat is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir or tipranavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain cobicistat interactions. Cobicistat and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A) isoforms. Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir and therefore enables increased anti-viral activity at a lower dosage. Cobicistat does not have any anti-HIV activity on its own. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Median peak plasma concentrations were observed at 3.5 hours post-dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97-98% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal plasma half-life of cobicistat is approximately 3 to 4 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse reactions reported during clinical trials were jaundice (13%), ocular icterus (15%), and nausea (12%). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Evotaz, Genvoya, Prezcobix, Rezolsta, Stribild, Tybost •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cobicistat •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cobicistat is a CYP3A inhibitor used to increase the systemic exposure of atazanavir or darunavir in combination with other antiretroviral agents in the treatment of HIV-1 infection.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cobicistat interact? Information: •Drug A: Adalimumab •Drug B: Cobicistat •Severity: MODERATE •Description: The metabolism of Cobicistat can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cobicistat is a CYP3A inhibitor indicated to increase systemic exposure of atazanavir or darunavir (once daily dosing regimen) in combination with other antiretroviral agents in the treatment of HIV-1 infection. It is not interchangeable with ritonavir to increase systemic exposure of darunavir 600 mg twice daily, fosamprenavir, saquinavir, or tipranavir due to lack of exposure data. The use of cobicistat is not recommended with darunavir 600 mg twice daily, fosamprenavir, saquinavir or tipranavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of ritonavir drug interactions to certain cobicistat interactions. Cobicistat and ritonavir when administered with either atazanavir or darunavir may result in different drug interactions when used with concomitant medications. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): No pharmacodynamics available •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A) isoforms. Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of CYP3A substrates atazanavir and darunavir and therefore enables increased anti-viral activity at a lower dosage. Cobicistat does not have any anti-HIV activity on its own. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Median peak plasma concentrations were observed at 3.5 hours post-dose. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 97-98% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cobicistat is metabolized by CYP3A and to a minor extent by CYP2D6 enzymes and does not undergo glucuronidation. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): With single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days, the mean percent of the administered dose excreted in feces and urine was 86.2% and 8.2%, respectively. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal plasma half-life of cobicistat is approximately 3 to 4 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse reactions reported during clinical trials were jaundice (13%), ocular icterus (15%), and nausea (12%). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Evotaz, Genvoya, Prezcobix, Rezolsta, Stribild, Tybost •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cobicistat •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cobicistat is a CYP3A inhibitor used to increase the systemic exposure of atazanavir or darunavir in combination with other antiretroviral agents in the treatment of HIV-1 infection. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cobimetinib interact?

•Drug A: Adalimumab •Drug B: Cobimetinib •Severity: MAJOR •Description: The metabolism of Cobimetinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cobimetinib is indicated in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. As a single agent, cobimetinib is also indicated for the treatment of adult patients with histiocytic neoplasms. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors become BRAF-inhibitor resistant due to reactivation of MAPK signaling. BRAF-inhibitor-resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, cobimetinib inhibited tumor cell growth. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (T max ) was 2.4 (range:1–24) hours, geometric mean steady-state AUC 0-24h was 4340 ng∙h/mL (61% CV) and C max was 273 ng/mL (60% CV). The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in healthy subjects. A high‐fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC and Cmax after a single 20 mg COTELLIC was administered to healthy subjects. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug). •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean apparent clearance (CL/F) was 13.8 L/h (61% CV). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cotellic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cobimetinib is an antineoplastic agent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway used to treat unresectable or metastatic melanoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Cobimetinib interact? Information: •Drug A: Adalimumab •Drug B: Cobimetinib •Severity: MAJOR •Description: The metabolism of Cobimetinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cobimetinib is indicated in combination with vemurafenib for the treatment of unresectable or metastatic melanoma with a BRAF V600E or V600K mutation. As a single agent, cobimetinib is also indicated for the treatment of adult patients with histiocytic neoplasms. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase 1 (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. Preclinical studies have demonstrated that this agent is effective in inhibiting the growth of tumor cells bearing a BRAF mutation, which has been found to be associated with many tumor types. A threonine-tyrosine kinase and a key component of the RAS/RAF/MEK/ERK signaling pathway that is frequently activated in human tumors, MEK1 is required for the transmission of growth-promoting signals from numerous receptor tyrosine kinases. Cobimetinib is used in combination with vemurafenib because the clinical benefit of a BRAF inhibitor is limited by intrinsic and acquired resistance. Reactivation of the MAPK pathway is a major contributor to treatment failure in BRAF-mutant melanomas, approximately ~80% of melanoma tumors become BRAF-inhibitor resistant due to reactivation of MAPK signaling. BRAF-inhibitor-resistant tumor cells are sensitive to MEK inhibition, therefore cobimetinib and vemurafenib will result in dual inhibition of BRAF and its downstream target, MEK. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cobimetinib is a reversible inhibitor of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E and K mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. In mice implanted with tumor cell lines expressing BRAF V600E, cobimetinib inhibited tumor cell growth. Cobimetinib and vemurafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of cobimetinib and vemurafenib resulted in increased apoptosis in vitro and reduced tumor growth in mouse implantation models of tumor cell lines harboring BRAF V600E mutations. Cobimetinib also prevented vemurafenib-mediated growth enhancement of a wild-type BRAF tumor cell line in an in vivo mouse implantation model. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Following oral dosing of 60 mg once daily in cancer patients, the median time to achieve peak plasma levels (T max ) was 2.4 (range:1–24) hours, geometric mean steady-state AUC 0-24h was 4340 ng∙h/mL (61% CV) and C max was 273 ng/mL (60% CV). The absolute bioavailability of COTELLIC was 46% (90% CI: 40%, 53%) in healthy subjects. A high‐fat meal (comprised of approximately 150 calories from protein, 250 calories from carbohydrate, and 500–600 calories from fat) had no effect on cobimetinib AUC and Cmax after a single 20 mg COTELLIC was administered to healthy subjects. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The estimated apparent volume of distribution was 806 L in cancer patients based on a population PK analysis. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cobimetinib is 95% bound to human plasma proteins in vitro, independent of drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cobimetinib is mainly metabolized via CYP3A oxidation and UGT2B7 glucuronidation with no major metabolites formed. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following oral administration of a single 20 mg radiolabeled cobimetinib dose, 76% of the dose was recovered in the feces (with 6.6% as unchanged drug) and 17.8% of the dose was recovered in the urine (with 1.6% as unchanged drug). •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean elimination half-life (t1/2) was 44 (range: 23–70) hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Following oral administration of COTELLIC 60 mg once daily in cancer patients, the mean apparent clearance (CL/F) was 13.8 L/h (61% CV). •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse effects (>20%) for cobimetinib are diarrhea, photosensitivity reactions, nausea, fever and vomiting. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cotellic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cobimetinib is an antineoplastic agent and selective inhibitor of the mitogen-activated extracellular kinase (MEK) pathway used to treat unresectable or metastatic melanoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Codeine interact?

•Drug A: Adalimumab •Drug B: Codeine •Severity: MODERATE •Description: The metabolism of Codeine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Codeine sulfate is a form of this drug that is commonly used. It is available in tablet form and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate. The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged 18 and above,. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): General effects Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression. Antitussive activity This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing. Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla. Effects on intestinal motility Codeine may reduce intestinal motility through both a local and possibly central mechanism of action. This may possibly lead to constipation. The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility. Effects on the central nervous system Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the mu opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine. Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system. Effects on blood pressure This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms. Effects on chronic cancer pain and other types of pain Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours. Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms,. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors. Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine. However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine. Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα i, causing a decrease in intracellular cAMP and Ca level. This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Absorption Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration. Food Effects When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine. Steady-state concentration The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 7-25% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6­ glucuronide (C6G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, codeine 6 glucuronide. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to norcodeine. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and_ morphine-6-glucuronide _(M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study. Renal impairment may decrease codeine clearance. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral LD50: 427 mg kg-1 (rat). Overdose/toxicity Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite. In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal,. Teratogenic effects This drug is classified as a pregnancy Category C drug. There are no adequate and well-controlled studies completed in pregnant women. Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus. Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose. Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification. Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison. Nonteratogenic effects Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery. Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs may be observed shortly following birth and may require specific treatment. Codeine (30 mg/kg) given subcutaneously to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth. The dose given was 0.8 times the maximum recommended human dose of 360 mg/day. The use in breastfeeding/nursing Codeine is secreted into human milk. The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ascomp, Cheratussin, Cheratussin Dac, Codar Ar, Codar D, Codar Gf, Codeine Contin, Covan, Damylin With Codeine, Fioricet With Codeine, Histex Ac, Linctus Codeine Blanc, M-clear Wc, M-end PE, Mar-cof BP, Mar-cof Cg, Mersyndol, Ninjacof Xg, Pseudodine C, Robaxacet-8, Robaxisal, Triacin-C, Trianal C, Triatec, Triatec-30, Triatec-8, Tusnel C, Tuxarin, Tuzistra, Tylenol With Codeine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Codein Codeína Codéine Codeine polistirex Codeinum Methylmorphine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Codeine is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Codeine interact? Information: •Drug A: Adalimumab •Drug B: Codeine •Severity: MODERATE •Description: The metabolism of Codeine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Codeine sulfate is a form of this drug that is commonly used. It is available in tablet form and indicated for the relief of mild to moderately severe pain, where the use of an opioid analgesic is appropriate. The solution form is used by itself or combined in a syrup with other drugs and is used as a cough suppressant in adults aged 18 and above,. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): General effects Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression. Antitussive activity This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing. Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla. Effects on intestinal motility Codeine may reduce intestinal motility through both a local and possibly central mechanism of action. This may possibly lead to constipation. The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility. Effects on the central nervous system Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the mu opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine. Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system. Effects on blood pressure This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms. Effects on chronic cancer pain and other types of pain Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours. Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms,. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors. Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine. However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine. Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα i, causing a decrease in intracellular cAMP and Ca level. This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Absorption Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration. Food Effects When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine. Steady-state concentration The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 7-25% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to codeine-6­ glucuronide (C6G) and by O-demethylation to morphine (about 5-10%) and N-demethylation to norcodeine (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, codeine 6 glucuronide. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to norcodeine. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are morphine-3-glucuronide (M3G) and_ morphine-6-glucuronide _(M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study. Renal impairment may decrease codeine clearance. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Oral LD50: 427 mg kg-1 (rat). Overdose/toxicity Symptoms of opioid toxicity may include confusion, somnolence, shallow breathing, constricted pupils, nausea, vomiting, constipation and a lack of appetite. In severe cases, symptoms of circulatory and respiratory depression may ensue, which may be life-threatening or fatal,. Teratogenic effects This drug is classified as a pregnancy Category C drug. There are no adequate and well-controlled studies completed in pregnant women. Codeine should only be used during pregnancy if the potential benefit outweighs the potential risk of the drug to the fetus. Codeine has shown embryolethal and fetotoxic effects in the hamster, rat as well as mouse models at about 2-4 times the maximum recommended human dose. Maternally toxic doses that were about 7 times the maximum recommended human dose of 360 mg/day, were associated with evidence of bone resorption and incomplete bone ossification. Codeine did not demonstrate evidence of embrytoxicity or fetotoxicity in the rabbit model at doses up to 2 times the maximum recommended human dose of 360 mg/day based on a body surface area comparison. Nonteratogenic effects Neonatal codeine withdrawal has been observed in infants born to addicted and non-addicted mothers who ingested codeine-containing medications in the days before delivery. Common symptoms of narcotic withdrawal include irritability, excessive crying, tremors, hyperreflexia, seizures, fever, vomiting, diarrhea, and poor feeding. These signs may be observed shortly following birth and may require specific treatment. Codeine (30 mg/kg) given subcutaneously to pregnant rats during gestation and for 25 days after delivery increased the rate of neonatal mortality at birth. The dose given was 0.8 times the maximum recommended human dose of 360 mg/day. The use in breastfeeding/nursing Codeine is secreted into human milk. The maternal use of codeine can potentially lead to serious adverse reactions, including death, in nursing infants. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ascomp, Cheratussin, Cheratussin Dac, Codar Ar, Codar D, Codar Gf, Codeine Contin, Covan, Damylin With Codeine, Fioricet With Codeine, Histex Ac, Linctus Codeine Blanc, M-clear Wc, M-end PE, Mar-cof BP, Mar-cof Cg, Mersyndol, Ninjacof Xg, Pseudodine C, Robaxacet-8, Robaxisal, Triacin-C, Trianal C, Triatec, Triatec-30, Triatec-8, Tusnel C, Tuxarin, Tuzistra, Tylenol With Codeine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Codein Codeína Codéine Codeine polistirex Codeinum Methylmorphine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Codeine is an opioid analgesic used to treat moderate to severe pain when the use of an opioid is indicated. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Conivaptan interact?

•Drug A: Adalimumab •Drug B: Conivaptan •Severity: MAJOR •Description: The metabolism of Conivaptan can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V 1A and V 2 receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V 2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular 1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V 2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V 1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Conivaptan is a dual AVP antagonist with nanomolar affinity for human arginine vasopressin V 1A and V 2 receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V 1a and V 2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Vaprisol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Conivaptan •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Conivaptan is an antidiuretic hormone inhibitor used to raise serum sodium levels.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Conivaptan interact? Information: •Drug A: Adalimumab •Drug B: Conivaptan •Severity: MAJOR •Description: The metabolism of Conivaptan can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of euvolemic or hypervolemic hyponatremia (e.g. the syndrome of inappropriate secretion of antidiuretic hormone, or in the setting of hypothyroidism, adrenal insufficiency, pulmonary disorders, etc.) in hospitalized patients. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Conivaptan is a nonpeptide, dual antagonist of arginine vasopressin (AVP) V 1A and V 2 receptors. The level of AVP in circulating blood is critical for the regulation of water and electrolyte balance and is usually elevated in both euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V 2 receptors, which are functionally coupled to aquaporin channels in the apical membrane of the collecting ducts of the kidney. These receptors help to maintain plasma osmolality within the normal range by increasing permeability of the renal collecting ducts to water. Vasopressin also causes vasoconstriction through its actions on vascular 1A receptors. The predominant pharmacodynamic effect of conivaptan in the treatment of hyponatremia is through its V 2 antagonism of AVP in the renal collecting ducts, an effect that results in aquaresis, or excretion of free water. Conivaptan's antagonist activity on V 1A receptors may also cause splanchnic vasodilation, resulting in possible hypotension or variceal bleeding in patients with cirrhosis. The pharmacodynamic effects of conivaptan include increased free water excretion (i.e., effective water clearance [EWC]) generally accompanied by increased net fluid loss, increased urine output, and decreased urine osmolality. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Conivaptan is a dual AVP antagonist with nanomolar affinity for human arginine vasopressin V 1A and V 2 receptors in vitro. This antagonism occurs in the renal collecting ducts, resulting in aquaresis, or excretion of free water. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): CYP3A4 is the sole cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four metabolites have been identified. The pharmacological activity of the metabolites at V 1a and V 2 receptors ranged from approximately 3-50% and 50-100% that of conivaptan, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Although no data on overdosage in humans are available, conivaptan has been administered as a 20 mg loading dose on Day 1 followed by continuous infusion of 80 mg/day for 4 days in hyponatremia patients and up to 120 mg/day for 2 days in CHF patients. No new toxicities were identified at these higher doses, but adverse events related to the pharmacologic activity of conivaptan, e.g. hypotension and thirst, occurred more frequently at these higher doses. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Vaprisol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Conivaptan •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Conivaptan is an antidiuretic hormone inhibitor used to raise serum sodium levels. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Conjugated estrogens interact?

•Drug A: Adalimumab •Drug B: Conjugated estrogens •Severity: MODERATE •Description: The metabolism of Conjugated estrogens can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): The conjugated estrogens are indicated for several different conditions including: Treatment of moderate to severe vasomotor symptoms due to menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Palliative treatment of breast cancer in appropriately selected patients with metastatic disease. Palliative treatment of androgen-dependent carcinoma of the prostate. Preventive therapy of postmenopausal osteoporosis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The binding of estrogens to the estrogen receptor produces the activation of nuclear receptors in order to bind to estrogen response elements in certain target genes. This mechanistic cascade results in histone acetylation, alteration of chromatin conformation and the initiation of transcription of certain specific drugs. In preclinical studies, the conjugated estrogens are known to have a similar estrogenic potency than estrone and the equilin components of the conjugated estrogens have similar potency in the liver when compared to bioidentical estradiol. It has also been tested and confirmed that conjugated estrogens present a selective estrogen receptor modulator profile which allows it to have a large beneficial effect on the bone and cardiovascular system. Clinically, the administration of conjugated estrogens is known to promote vasomotor stability, maintain genitourinary function, and normal growth and development of female sex hormones. It has also been shown to prevent accelerated bone loss by inhibiting bone resorption and restoring the balance of bone resorption. In the hormonal area, it is shown to inhibit luteinizing hormone and decrease the serum concentration of testosterone. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The conjugated estrogens, equally to the normal physiological estrogen, work by agonistically binding to the estrogen receptors alpha and beta. The estrogen receptors vary in quantity and proportion according to the tissues and hence, the activity of this conjugated estrogens is very variable. The activity made by the conjugated estrogens is driven by the increase in the synthesis of DNA, RNA and various proteins in responsive tissues which in order will reduce the release of gonadotropin-releasing hormone, follicle-stimulating hormone and leuteinizing hormone. The specific mechanism of action cannot be described only in terms of total estrogenic action as the pharmacokinetic profile, the tissue specificity and the tissue metabolism is different for each component of the product. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The conjugated estrogens are well absorbed in the gastrointestinal tract and the maximum plasma concentration of the conjugated estrogens is reached after 7 hours depending on the estrone component. The maximal plasma concentration of conjugated estrogens after multiple doses of 0.45 mg is reported to be of 2.6 ng/ml with an AUC in the steady state of 35 ng.h/ml. Unconjugated estrogens are known to be cleared from the circulation at a faster rate than their ester forms. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The physiological distribution of estrogens in the body is very similar to what is seen in endogenous estrogens and hence, it is widely distributed. The conjugated estrogens are mainly found in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Conjugated estrogens are bound to plasma proteins and this bound state can represent around 50-80% of the administered dose. It circulates in the blood mainly bound to sex-hormone binding globulin and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The conjugated estrogens are metabolized by a number of different pathways. One of the metabolic pathways of the conjugated estrogens is driven by the action of the cytochrome isoenzyme CYP3A4. On the other hand, the conjugated estrogens can also be processed by a dynamic equilibrium of metabolic interconversion and sulfate conjugation. Some of the principal metabolic reactions of the conjugated estrogens are driven by the conversion of 17beta-estradiol to estrone and the further change to estriol. A portion of the administered conjugated estrogens will remain in the blood as sulfate conjugates which serve as a circulating reservoir for the generation of new estrogens. In the endometrium, equilin is metabolized to 2-hydroxy and 4-hydroxy equilin as well as 2-hydroxy and 4-hydroxy estradiol. This hydroxylation process is very large in various of the components of the conjugated estrogens and hence, the major metabolites in urine are known to be 17-ketosteroid-16-alpha-hydroxy estrone, 16-alpha-hydroxy-17-beta-dihydro equilin and 16-alpha-hydroxy-17-beta-dihydroequilenin. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The conjugated estrogens are eliminated mainly in the urine. In this renal elimination, it is possible to find 17 beta-estradiol, estrone, estriol, as well as the glucuronide and sulfate conjugates of the estrogens. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The median half-life of the conjugated estrogens is reported to be of 17 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The reported normal clearance rate for estrogens is of approximately 615 L/m2. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The reported oral LD50 in the rat is of more than 5000 mg/kg. Serious overdosage symptoms have not been reported. There have been only reports of nausea, vomiting, and withdrawal in bleeding in females. Long-term continuous administration of estrogens is correlated to increased risk on the incidence of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Congest, Duavee, Duavive, Premarin, Premphase 28 Day, Prempro 0.625/2.5 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Conjugated estrogens is a mixture of estrogens used in estrogen replacement therapy for menopause and hypoestrogenism, used in the treatment of various malignancies, and used in the treatment of postmenopausal osteoporosis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Conjugated estrogens interact? Information: •Drug A: Adalimumab •Drug B: Conjugated estrogens •Severity: MODERATE •Description: The metabolism of Conjugated estrogens can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): The conjugated estrogens are indicated for several different conditions including: Treatment of moderate to severe vasomotor symptoms due to menopause. Treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. Treatment of hypoestrogenism due to hypogonadism, castration or primary ovarian failure. Palliative treatment of breast cancer in appropriately selected patients with metastatic disease. Palliative treatment of androgen-dependent carcinoma of the prostate. Preventive therapy of postmenopausal osteoporosis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The binding of estrogens to the estrogen receptor produces the activation of nuclear receptors in order to bind to estrogen response elements in certain target genes. This mechanistic cascade results in histone acetylation, alteration of chromatin conformation and the initiation of transcription of certain specific drugs. In preclinical studies, the conjugated estrogens are known to have a similar estrogenic potency than estrone and the equilin components of the conjugated estrogens have similar potency in the liver when compared to bioidentical estradiol. It has also been tested and confirmed that conjugated estrogens present a selective estrogen receptor modulator profile which allows it to have a large beneficial effect on the bone and cardiovascular system. Clinically, the administration of conjugated estrogens is known to promote vasomotor stability, maintain genitourinary function, and normal growth and development of female sex hormones. It has also been shown to prevent accelerated bone loss by inhibiting bone resorption and restoring the balance of bone resorption. In the hormonal area, it is shown to inhibit luteinizing hormone and decrease the serum concentration of testosterone. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The conjugated estrogens, equally to the normal physiological estrogen, work by agonistically binding to the estrogen receptors alpha and beta. The estrogen receptors vary in quantity and proportion according to the tissues and hence, the activity of this conjugated estrogens is very variable. The activity made by the conjugated estrogens is driven by the increase in the synthesis of DNA, RNA and various proteins in responsive tissues which in order will reduce the release of gonadotropin-releasing hormone, follicle-stimulating hormone and leuteinizing hormone. The specific mechanism of action cannot be described only in terms of total estrogenic action as the pharmacokinetic profile, the tissue specificity and the tissue metabolism is different for each component of the product. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The conjugated estrogens are well absorbed in the gastrointestinal tract and the maximum plasma concentration of the conjugated estrogens is reached after 7 hours depending on the estrone component. The maximal plasma concentration of conjugated estrogens after multiple doses of 0.45 mg is reported to be of 2.6 ng/ml with an AUC in the steady state of 35 ng.h/ml. Unconjugated estrogens are known to be cleared from the circulation at a faster rate than their ester forms. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The physiological distribution of estrogens in the body is very similar to what is seen in endogenous estrogens and hence, it is widely distributed. The conjugated estrogens are mainly found in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Conjugated estrogens are bound to plasma proteins and this bound state can represent around 50-80% of the administered dose. It circulates in the blood mainly bound to sex-hormone binding globulin and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The conjugated estrogens are metabolized by a number of different pathways. One of the metabolic pathways of the conjugated estrogens is driven by the action of the cytochrome isoenzyme CYP3A4. On the other hand, the conjugated estrogens can also be processed by a dynamic equilibrium of metabolic interconversion and sulfate conjugation. Some of the principal metabolic reactions of the conjugated estrogens are driven by the conversion of 17beta-estradiol to estrone and the further change to estriol. A portion of the administered conjugated estrogens will remain in the blood as sulfate conjugates which serve as a circulating reservoir for the generation of new estrogens. In the endometrium, equilin is metabolized to 2-hydroxy and 4-hydroxy equilin as well as 2-hydroxy and 4-hydroxy estradiol. This hydroxylation process is very large in various of the components of the conjugated estrogens and hence, the major metabolites in urine are known to be 17-ketosteroid-16-alpha-hydroxy estrone, 16-alpha-hydroxy-17-beta-dihydro equilin and 16-alpha-hydroxy-17-beta-dihydroequilenin. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The conjugated estrogens are eliminated mainly in the urine. In this renal elimination, it is possible to find 17 beta-estradiol, estrone, estriol, as well as the glucuronide and sulfate conjugates of the estrogens. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The median half-life of the conjugated estrogens is reported to be of 17 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The reported normal clearance rate for estrogens is of approximately 615 L/m2. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The reported oral LD50 in the rat is of more than 5000 mg/kg. Serious overdosage symptoms have not been reported. There have been only reports of nausea, vomiting, and withdrawal in bleeding in females. Long-term continuous administration of estrogens is correlated to increased risk on the incidence of carcinomas of the breast, uterus, cervix, vagina, testis, and liver. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Congest, Duavee, Duavive, Premarin, Premphase 28 Day, Prempro 0.625/2.5 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Conjugated estrogens is a mixture of estrogens used in estrogen replacement therapy for menopause and hypoestrogenism, used in the treatment of various malignancies, and used in the treatment of postmenopausal osteoporosis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Copanlisib interact?

•Drug A: Adalimumab •Drug B: Copanlisib •Severity: MAJOR •Description: The metabolism of Copanlisib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Copanlisib is indicated for the treatment of adults with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. This indication was granted under accelerated approval; thus, continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Copanlisib is a kinase inhibitor with anti-tumour and pro-apoptotic activity in various tumour cell lines and xenograft models. Copanlisib causes an elevation in plasma glucose levels. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Phosphatidylinositol-3-kinase (PI3K) signalling pathway is implicated in cell proliferation and survival, as well as resistance to chemotherapeutic agents. PI3K isoforms are often overexpressed in B-cell malignancies, including follicular lymphoma. Copanlisib is a class I PI3K inhibitor with preferential activity against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. It binds with IC 50 values of 0.5, 3.7, 6.4, and 0.7 nmol/L against class I PI3K-α, β, γ, and δ isoforms, respectively. Copanlisibinduces tumour cell death by apoptosis, blocks cell cycle progression, and inhibits the proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell signalling pathways, including B-cell receptor (BCR) signalling, CXCR12-mediated chemotaxis of malignant B cells, and NFκB signalling in lymphoma cell lines. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of copanlisib increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics (PK). There is no time-dependency and no accumulation in the pharmacokinetics of copanlisib. The geometric mean (range) steady state copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for C max and 1570 (range: 536 to 3410; SD: 338) ng x hr/mL for AUC 0-25h. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Copanlisib is 84.2% bound to plasma proteins, mainly to serum albumin. The in vitro mean blood-to-plasma ratio is 1.7, with a range from 1.5 to 2.1. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Copanlisib is primarily metabolized by CYP3A (>90%) and to a lesser extent, CYP1A1 (<10%). The M1 metabolite accounts for 5% of total radioactivity in plasma and has a pharmacological activity that is comparable to that of the parent compound. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): In humans, approximately half of copanlisib is excreted as unchanged parent compound and the other half is excreted as metabolites. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation accounted for 41% of the administered dose. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The LD 50 of copanlisib dihydrochloride in male and female rats after a single intravenous dose administration was >23.0 mg/kg, which corresponds to 20.0 mg/kg copanlisib. There is no information on copanlisib overdose. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aliqopa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Copanlisib is a PI3K inhibitor used to treat relapsed follicular lymphoma in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Copanlisib interact? Information: •Drug A: Adalimumab •Drug B: Copanlisib •Severity: MAJOR •Description: The metabolism of Copanlisib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Copanlisib is indicated for the treatment of adults with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies. This indication was granted under accelerated approval; thus, continued approval may be contingent upon verification and description of clinical benefit in a confirmatory trial. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Copanlisib is a kinase inhibitor with anti-tumour and pro-apoptotic activity in various tumour cell lines and xenograft models. Copanlisib causes an elevation in plasma glucose levels. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Phosphatidylinositol-3-kinase (PI3K) signalling pathway is implicated in cell proliferation and survival, as well as resistance to chemotherapeutic agents. PI3K isoforms are often overexpressed in B-cell malignancies, including follicular lymphoma. Copanlisib is a class I PI3K inhibitor with preferential activity against PI3K-α and PI3K-δ isoforms expressed in malignant B cells. It binds with IC 50 values of 0.5, 3.7, 6.4, and 0.7 nmol/L against class I PI3K-α, β, γ, and δ isoforms, respectively. Copanlisibinduces tumour cell death by apoptosis, blocks cell cycle progression, and inhibits the proliferation of primary malignant B cell lines. Copanlisib inhibits several key cell signalling pathways, including B-cell receptor (BCR) signalling, CXCR12-mediated chemotaxis of malignant B cells, and NFκB signalling in lymphoma cell lines. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The area under the plasma concentration-time curve (AUC) and maximum plasma concentration (C max ) of copanlisib increase dose-proportionally over 5 to 93 mg (0.08 to 1.55 times the approved recommended dose) absolute dose range and exhibit linear pharmacokinetics (PK). There is no time-dependency and no accumulation in the pharmacokinetics of copanlisib. The geometric mean (range) steady state copanlisib exposure at 0.8 mg/kg (approximately the approved recommended dose of 60 mg) are 463 (range: 105 to 1670; SD: 584) ng/mL for C max and 1570 (range: 536 to 3410; SD: 338) ng x hr/mL for AUC 0-25h. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The geometric mean volume of distribution is 871 (range: 423 to 2150; SD: 479) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Copanlisib is 84.2% bound to plasma proteins, mainly to serum albumin. The in vitro mean blood-to-plasma ratio is 1.7, with a range from 1.5 to 2.1. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Copanlisib is primarily metabolized by CYP3A (>90%) and to a lesser extent, CYP1A1 (<10%). The M1 metabolite accounts for 5% of total radioactivity in plasma and has a pharmacological activity that is comparable to that of the parent compound. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): In humans, approximately half of copanlisib is excreted as unchanged parent compound and the other half is excreted as metabolites. Following a single intravenous dose of 12 mg (0.2 times the recommended approved dose) radiolabeled copanlisib, approximately 64% of the administered dose was recovered in feces and 22% in urine within 20 to 34 days. Unchanged copanlisib represented approximately 30% of the administered dose in feces and 15% in urine. Metabolites resulting from CYP450-mediated oxidation accounted for 41% of the administered dose. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The geometric mean terminal elimination half-life of copanlisib is 39.1 (range: 14.6 to 82.4; SD: 15.0) hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric mean clearance is 17.9 (range: 7.3 to 51.4; SD: 8.5) L/hr. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The LD 50 of copanlisib dihydrochloride in male and female rats after a single intravenous dose administration was >23.0 mg/kg, which corresponds to 20.0 mg/kg copanlisib. There is no information on copanlisib overdose. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aliqopa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Copanlisib is a PI3K inhibitor used to treat relapsed follicular lymphoma in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Corticotropin interact?

•Drug A: Adalimumab •Drug B: Corticotropin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Corticotropin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For use as a diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Purified corticotropin for injection is indicated for a variety of allergic and autoimmune conditions. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Corticotropin acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. Corticotropin stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also sex steroids (androgens). Corticotropin is also related to the circadian rhythm in many organisms. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): As a diagnostic aid (adrenocortical function), corticotropin combines with a specific receptor on the adrenal cell plasma membrane. In patients with normal adrenocortical function, it stimulates the initial reaction involved in the synthesis of adrenal steroids (including cortisol, cortisone, weak androgenic substances, and a limited quantity of aldosterone) from cholesterol by increasing the quantity of cholesterol within the mitochondria. Corticotropin does not significantly increase serum cortisol concentrations in patients with primary adrenocortical insufficiency (Addison's disease). The mechanism of action of corticotropin in the treatment of infantile myoclonic seizures is unknown. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Corticotropin is rapidly absorbed following intramuscular administration; the repository dosage form is slowly absorbed over approximately 8 to 16 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): About 15 minutes following intravenous administration. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Acthar, Cortrophin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Corticotropin is a diagnostic agent used in the screening of patients presumed to have adrenocortical insufficiency.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Corticotropin interact? Information: •Drug A: Adalimumab •Drug B: Corticotropin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Corticotropin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For use as a diagnostic agent in the screening of patients presumed to have adrenocortical insufficiency. Purified corticotropin for injection is indicated for a variety of allergic and autoimmune conditions. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Corticotropin acts through the stimulation of cell surface ACTH receptors, which are primarily located on the adrenocortical cells. Corticotropin stimulates the cortex of the adrenal gland and boosts the synthesis of corticosteroids, mainly glucocorticoids but also sex steroids (androgens). Corticotropin is also related to the circadian rhythm in many organisms. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): As a diagnostic aid (adrenocortical function), corticotropin combines with a specific receptor on the adrenal cell plasma membrane. In patients with normal adrenocortical function, it stimulates the initial reaction involved in the synthesis of adrenal steroids (including cortisol, cortisone, weak androgenic substances, and a limited quantity of aldosterone) from cholesterol by increasing the quantity of cholesterol within the mitochondria. Corticotropin does not significantly increase serum cortisol concentrations in patients with primary adrenocortical insufficiency (Addison's disease). The mechanism of action of corticotropin in the treatment of infantile myoclonic seizures is unknown. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Corticotropin is rapidly absorbed following intramuscular administration; the repository dosage form is slowly absorbed over approximately 8 to 16 hours. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): About 15 minutes following intravenous administration. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Acthar, Cortrophin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Corticotropin is a diagnostic agent used in the screening of patients presumed to have adrenocortical insufficiency. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Cortisone acetate interact?

•Drug A: Adalimumab •Drug B: Cortisone acetate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cortisone acetate. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cortisone acetate is indicated to treat a wide variety of endocrine, rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, and gastrointestinal diseases and disorders. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. The duration of action is moderate as it is generally given once daily. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Data regarding the clearance of cortisone acetate is not readily available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cortisone acetate Cortone acetate •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cortisone acetate is a steroid hormone used for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and endocrine disorders associated with inadequate production of steroid hormones.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Cortisone acetate interact? Information: •Drug A: Adalimumab •Drug B: Cortisone acetate •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cortisone acetate. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cortisone acetate is indicated to treat a wide variety of endocrine, rheumatic, collagen, dermatologic, allergic, ophthalmic, respiratory, hematologic, neoplastic, edematous, and gastrointestinal diseases and disorders. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Corticosteroids bind to the glucocorticoid receptor, inhibiting pro-inflammatory signals, and promoting anti-inflammatory signals. The duration of action is moderate as it is generally given once daily. Corticosteroids have a wide therapeutic window as patients may require doses that are multiples of what the body naturally produces. Patients taking corticosteroids should be counselled regarding the risk of hypothalamic-pituitary-adrenal axis suppression and increased susceptibility to infections. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation. Corticosteroids binding to the glucocorticoid receptor mediates changes in gene expression that lead to multiple downstream effects over hours to days. Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10. Lower doses of corticosteroids provide an anti-inflammatory effect, while higher doses are immunosuppressive. High doses of glucocorticoids for an extended period bind to the mineralocorticoid receptor, raising sodium levels and decreasing potassium levels. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): No absorption available •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Corticosteroids are generally bound to corticosteroid binding globulin and serum albumin in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Corticosteroids are eliminated predominantly in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): No half-life available •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Data regarding the clearance of cortisone acetate is not readily available. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding acute overdoses of glucocorticoids are rare. Chronic high doses of glucocorticoids can lead to the development of cataract, glaucoma, hypertension, water retention, hyperlipidemia, peptic ulcer, pancreatitis, myopathy, osteoporosis, mood changes, psychosis, dermal atrophy, allergy, acne, hypertrichosis, immune suppression, decreased resistance to infection, moon face, hyperglycemia, hypocalcemia, hypophosphatemia, metabolic acidosis, growth suppression, and secondary adrenal insufficiency. Overdose may be treated by adjusting the dose or stopping the corticosteroid as well as initiating symptomatic and supportive treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Cortisone acetate Cortone acetate •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cortisone acetate is a steroid hormone used for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses and endocrine disorders associated with inadequate production of steroid hormones. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Crizotinib interact?

•Drug A: Adalimumab •Drug B: Crizotinib •Severity: MAJOR •Description: The metabolism of Crizotinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Crizotinib is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. Additionally, crizotinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In a phase I study, 37 patients with a variety of solid-tumor cancers refractory to therapy received 50 to 300 mg of crizotinib daily or twice daily. In this group, two patients with non-small cell lung cancer (NSCLC) exhibiting echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations responded to therapy; therefore, following studies focused on patients with advanced ALK-positive disease. In this group of patients, the 6-month progression-free survival among crizotinib users was approximately 72%. When compared to ALK mutation-positive patients that did not receive crizotinib, ALK mutation-positive patients treated with crizotinib had a higher two-year overall survival rate (54% vs 36%). The use of crizotinib may lead to hepatotoxicity, interstitial lung disease (ILD), pneumonitis, QT interval prolongation, bradycardia, severe visual loss, ​​embryo-fetal toxicity and gastrointestinal toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT). •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Crizotinib is a tyrosine kinase receptor inhibitor that targets anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). When activated, ALK inhibits apoptosis and promotes cell proliferation, and ALK-gene translocations can lead to the expression of oncogenic fusion proteins. A small portion of non-small cell lung cancer (NSCLC) patients have ALK-positive tumors. Most of these cases are characterized by the fusion of ALK with the chimeric protein echinoderm microtubule-associated protein-like 4 (EML4), resulting in increased kinase activity. Crizotinib inhibits ALK by inhibiting its phosphorylation and creating an inactive protein conformation. This ultimately lowers the proliferation of cells carrying this genetic mutation and tumour survivability. In vitro assays on tumor cell lines demonstrated that crizotinib inhibits ALK, ROS1, and c-Met phosphorylation in a concentration-dependent manner. In vivo studies in mice with tumor xenografts that expressed EML4- or nucleophosmin (NPM)-ALK fusion proteins or c-Met showed that crizotinib has antitumor activity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and C max increased in a dose-proportional manner. A single crizotinib dose of crizotinib is absorbed with a median t max 4 to 6 hours. In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng⋅hr/mL, the mean C max was 99.60 ng/mL, and the median t max was 5.0 hours. The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. High-fat meals reduce the AUC 0-INF and C max of crizotinib by approximately 14%. Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics. In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Crizotinib is 91% bound to plasma protein. In vitro studies suggest that this is not affected by drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation. Non-metabolic elimination, such as biliary excretion, can not be excluded. PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified. In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3- to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5- to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following single doses of crizotinib, the plasma terminal half-life was 42 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr),, possibly due to CYP3A auto-inhibition. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily). This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors. The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures. There is no antidote for crizotinib. In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic. Carcinogenicity studies with crizotinib have not been performed. In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles. In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Xalkori •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Crizotinib is a receptor tyrosine kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) where the tumors have been confirmed to be anaplastic lymphoma kinase (ALK), or ROS1-positive.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Crizotinib interact? Information: •Drug A: Adalimumab •Drug B: Crizotinib •Severity: MAJOR •Description: The metabolism of Crizotinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Crizotinib is a kinase inhibitor indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK) or ROS1-positive as detected by an FDA-approved test. Crizotinib is also indicated for the treatment of relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL) that is ALK-positive in pediatric patients 1 year of age and older and young adults. The safety and efficacy of crizotinib have not been established in older adults with relapsed or refractory, systemic ALK-positive ALCL. Additionally, crizotinib is indicated for the treatment of adult and pediatric patients 1 year of age and older with unresectable, recurrent, or refractory inflammatory myofibroblastic tumor (IMT) that is ALK-positive. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In a phase I study, 37 patients with a variety of solid-tumor cancers refractory to therapy received 50 to 300 mg of crizotinib daily or twice daily. In this group, two patients with non-small cell lung cancer (NSCLC) exhibiting echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) mutations responded to therapy; therefore, following studies focused on patients with advanced ALK-positive disease. In this group of patients, the 6-month progression-free survival among crizotinib users was approximately 72%. When compared to ALK mutation-positive patients that did not receive crizotinib, ALK mutation-positive patients treated with crizotinib had a higher two-year overall survival rate (54% vs 36%). The use of crizotinib may lead to hepatotoxicity, interstitial lung disease (ILD), pneumonitis, QT interval prolongation, bradycardia, severe visual loss, ​​embryo-fetal toxicity and gastrointestinal toxicity in pediatric and young adult patients with anaplastic large cell lymphoma (ALCL) or pediatric patients with inflammatory myofibroblastic tumor (IMT). •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Crizotinib is a tyrosine kinase receptor inhibitor that targets anaplastic lymphoma kinase (ALK), hepatocyte growth factor receptor (HGFR, c-MET), ROS1 (c-ros), and Recepteur d'Origine Nantais (RON). When activated, ALK inhibits apoptosis and promotes cell proliferation, and ALK-gene translocations can lead to the expression of oncogenic fusion proteins. A small portion of non-small cell lung cancer (NSCLC) patients have ALK-positive tumors. Most of these cases are characterized by the fusion of ALK with the chimeric protein echinoderm microtubule-associated protein-like 4 (EML4), resulting in increased kinase activity. Crizotinib inhibits ALK by inhibiting its phosphorylation and creating an inactive protein conformation. This ultimately lowers the proliferation of cells carrying this genetic mutation and tumour survivability. In vitro assays on tumor cell lines demonstrated that crizotinib inhibits ALK, ROS1, and c-Met phosphorylation in a concentration-dependent manner. In vivo studies in mice with tumor xenografts that expressed EML4- or nucleophosmin (NPM)-ALK fusion proteins or c-Met showed that crizotinib has antitumor activity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In patients with pancreatic, colorectal, sarcoma, anaplastic large-cell lymphoma and non-small cell lung cancer (NSCLC) treated with crizotinib doses ranging from 100 mg once a day to 300 mg twice a day, the mean AUC and C max increased in a dose-proportional manner. A single crizotinib dose of crizotinib is absorbed with a median t max 4 to 6 hours. In patients receiving multiple doses of crizotinib 250 mg twice daily (n=167), the mean AUC was is 2321.00 ng⋅hr/mL, the mean C max was 99.60 ng/mL, and the median t max was 5.0 hours. The mean absolute bioavailability of crizotinib is 43%, ranging from 32% to 66%. High-fat meals reduce the AUC 0-INF and C max of crizotinib by approximately 14%. Age, sex at birth, and ethnicity (Asian vs non-Asian patients) did not have a clinically significant effect on crizotinib pharmacokinetics. In patients less than 18 years old, higher body weight was associated with a lower crizotinib exposure. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Following a single intravenous dose, the mean volume of distribution (Vss) of crizotinib was 1772 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Crizotinib is 91% bound to plasma protein. In vitro studies suggest that this is not affected by drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Crizotinib is mainly metabolized in the liver by CYP3A4 and CYP3A5, and undergoes an O-dealkylation, with subsequent phase 2 conjugation. Non-metabolic elimination, such as biliary excretion, can not be excluded. PF-06260182 (with two constituent diastereomers, PF-06270079 and PF-06270080) is the only active metabolite of crizotinib that has been identified. In vitro studies suggest that, compared to crizotinib, PF-06270079 and PF-06270080 are approximately 3- to 8-fold less potent against anaplastic lymphoma kinase (ALK) and 2.5- to 4-fold less potent against Hepatocyte Growth Factor Receptor (HGFR, c-Met). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After administering a single 250 mg radiolabeled crizotinib dose to healthy subjects, 63% and 22% of the administered dose were recovered in feces and urine. Unchanged crizotinib represented approximately 53% and 2.3% of the administered dose in feces and urine, respectively. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following single doses of crizotinib, the plasma terminal half-life was 42 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): At steady-state (250 mg twice daily), crizotinib has a mean apparent clearance (CL/F) of 60 L/hr. This value is lower than the one detected after a single 250 mg oral dose (100 L/hr),, possibly due to CYP3A auto-inhibition. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The maximum tolerated dose of crizotinib is the same as the recommended dosing regimen (250 mg twice daily). This was defined based on a phase 1 dose-escalation study in patients with advanced solid tumors. The treatment of crizotinib overdoses should consist of symptomatic treatment and other supportive measures. There is no antidote for crizotinib. In vitro and in vivo studies have shown that crizotinib is genotoxic, and the Ames test showed that crizotinib was not mutagenic. Carcinogenicity studies with crizotinib have not been performed. In female rats, 500 mg/kg/day (approximately 10 times the recommended human dose based on body surface area) of crizotinib for 3 days induced single-cell necrosis of ovarian follicles. In male rats, 50 mg/kg/day of crizotinib (greater than 1.7 times the recommended human dose) for 28 days induced testicular pachytene spermatocyte degeneration. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Xalkori •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Crizotinib is a receptor tyrosine kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC) where the tumors have been confirmed to be anaplastic lymphoma kinase (ALK), or ROS1-positive. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Cyclobenzaprine interact?

•Drug A: Adalimumab •Drug B: Cyclobenzaprine •Severity: MODERATE •Description: The metabolism of Cyclobenzaprine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cyclobenzaprine is indicated as a short-term (2-3 weeks) adjunct therapy, along with rest and physical therapy, for relief of muscle spasm associated with acute, painful musculoskeletal conditions. It has not been found effective in the treatment of spasticity originating from cerebral or spinal cord disease, or spasticity in children with cerebral palsy. Cyclobenzaprine is also occasionally used off-label for reducing pain and sleep disturbances in patients with fibromyalgia. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cyclobenzaprine is a skeletal muscle relaxant that works on areas of the brainstem to reduce skeletal muscle spasm, though its exact pharmacodynamic behaviour is currently unclear. Despite its long half-life, it is relatively short-acting with a typical duration of action of 4-6 hours. Cyclobenzaprine has been reported to contribute to the development of serotonin syndrome when used in combination with other serotonergic medications. Symptoms of serotonin syndrome may include autonomic instability, changes to mental status, neuromuscular abnormalities, or gastrointestinal symptoms - treatment with cyclobenzaprine should be discontinued immediately if any of these reactions occur during therapy. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of action of cyclobenzaprine has not been fully elucidated in humans, and much of the information available regarding its mechanism has been ascertained from early animal studies. There is some evidence that cyclobenzaprine exerts its effects at the supraspinal level, specifically within the locus coeruleus of the brainstem, with little-to-no action at neuromuscular junctions or directly on skeletal musculature. Action on the brainstem is thought to result in diminished activity of efferent alpha and gamma motor neurons, likely mediated by inhibition of coeruleus-spinal or reticulospinal pathways, and ultimately depressed spinal cord interneuron activity. More recently it has been suggested that inhibition of descending serotonergic pathways in the spinal cord via action on 5-HT2 receptors may contribute to cyclobenzaprine’s observed effects. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and 0.55. C max is between 5-35 ng/mL and is achieved after 4 hours (T max ). AUC over an 8 hour dosing interval was reported to be approximately 177 ng.hr/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of cyclobenzaprine is approximately 146 L. The combination of high plasma clearance despite a relatively long half-life observed with cyclobenzaprine is suggestive of extensive tissue distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cyclobenzaprine is approximately 93% protein bound in plasma. It has been identified as specifically having a high affinity for human serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cyclobenzaprine is extensively metabolized in the liver via both oxidative and conjugative pathways. Oxidative metabolism, mainly N-demethylation, is catalyzed primarily by CYP3A4 and CYP1A2 (with CYP2D6 implicated to a lesser extent) and is responsible for the major metabolite desmethylcyclobenzaprine. Cyclobenzaprine also undergoes N-glucuronidation in the liver catalyzed by UGT1A4 and UGT2B10, and has been shown to undergo enterohepatic circulation. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After administration of a radio-labeled dose of cyclobenzaprine, 38-51% of radioactivity was excreted in the urine while 14-15% was excreted in the feces. Cyclobenzaprine is highly metabolized, with only approximately 1% of this same radio-labeled dose recovered in the urine as unchanged drug. Metabolites excreted in the urine are likely water-soluble glucuronide conjugates. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The effective half-life of cyclobenzaprine in young healthy subjects is approximately 18 hours. These values are extended in the elderly and those with hepatic insufficiency, with a mean effective half-life of 33.4 hours and 46.2 hours in these groups, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The approximate plasma clearance of cyclobenzaprine is 0.7 L/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 of cyclobenzaprine in mice and rats is 338 mg/kg and 425 mg/kg, respectively. Signs of overdose may develop rapidly after ingestion and commonly include significant drowsiness and tachycardia, with less common manifestations including tremor, agitation, ataxia, GI upset, and other CNS effects such as confusion and hallucinations. Potentially critical manifestations, though rare, include cardiac arrest or dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. As the management of cyclobenzaprine overdose is complex and ever-changing, it is recommended that a poison control center be consulted prior to treatment. Typical management involves gastrointestinal decontamination, close cardiac monitoring, and monitoring for signs of CNS or respiratory depression. As cyclobenzaprine exists in relatively low concentrations in plasma, monitoring of drug plasma levels should not guide management and dialysis is likely of no value. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Amrix, Fexmid, Flexeril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciclobenzaprina Cyclobenzaprine Cyclobenzaprinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cyclobenzaprine is a skeletal muscle relaxant that works on the brainstem to treat muscle spasms of local origin.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Cyclobenzaprine interact? Information: •Drug A: Adalimumab •Drug B: Cyclobenzaprine •Severity: MODERATE •Description: The metabolism of Cyclobenzaprine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cyclobenzaprine is indicated as a short-term (2-3 weeks) adjunct therapy, along with rest and physical therapy, for relief of muscle spasm associated with acute, painful musculoskeletal conditions. It has not been found effective in the treatment of spasticity originating from cerebral or spinal cord disease, or spasticity in children with cerebral palsy. Cyclobenzaprine is also occasionally used off-label for reducing pain and sleep disturbances in patients with fibromyalgia. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cyclobenzaprine is a skeletal muscle relaxant that works on areas of the brainstem to reduce skeletal muscle spasm, though its exact pharmacodynamic behaviour is currently unclear. Despite its long half-life, it is relatively short-acting with a typical duration of action of 4-6 hours. Cyclobenzaprine has been reported to contribute to the development of serotonin syndrome when used in combination with other serotonergic medications. Symptoms of serotonin syndrome may include autonomic instability, changes to mental status, neuromuscular abnormalities, or gastrointestinal symptoms - treatment with cyclobenzaprine should be discontinued immediately if any of these reactions occur during therapy. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of action of cyclobenzaprine has not been fully elucidated in humans, and much of the information available regarding its mechanism has been ascertained from early animal studies. There is some evidence that cyclobenzaprine exerts its effects at the supraspinal level, specifically within the locus coeruleus of the brainstem, with little-to-no action at neuromuscular junctions or directly on skeletal musculature. Action on the brainstem is thought to result in diminished activity of efferent alpha and gamma motor neurons, likely mediated by inhibition of coeruleus-spinal or reticulospinal pathways, and ultimately depressed spinal cord interneuron activity. More recently it has been suggested that inhibition of descending serotonergic pathways in the spinal cord via action on 5-HT2 receptors may contribute to cyclobenzaprine’s observed effects. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The oral bioavailability of cyclobenzaprine has been estimated to be between 0.33 and 0.55. C max is between 5-35 ng/mL and is achieved after 4 hours (T max ). AUC over an 8 hour dosing interval was reported to be approximately 177 ng.hr/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of cyclobenzaprine is approximately 146 L. The combination of high plasma clearance despite a relatively long half-life observed with cyclobenzaprine is suggestive of extensive tissue distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Cyclobenzaprine is approximately 93% protein bound in plasma. It has been identified as specifically having a high affinity for human serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cyclobenzaprine is extensively metabolized in the liver via both oxidative and conjugative pathways. Oxidative metabolism, mainly N-demethylation, is catalyzed primarily by CYP3A4 and CYP1A2 (with CYP2D6 implicated to a lesser extent) and is responsible for the major metabolite desmethylcyclobenzaprine. Cyclobenzaprine also undergoes N-glucuronidation in the liver catalyzed by UGT1A4 and UGT2B10, and has been shown to undergo enterohepatic circulation. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After administration of a radio-labeled dose of cyclobenzaprine, 38-51% of radioactivity was excreted in the urine while 14-15% was excreted in the feces. Cyclobenzaprine is highly metabolized, with only approximately 1% of this same radio-labeled dose recovered in the urine as unchanged drug. Metabolites excreted in the urine are likely water-soluble glucuronide conjugates. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The effective half-life of cyclobenzaprine in young healthy subjects is approximately 18 hours. These values are extended in the elderly and those with hepatic insufficiency, with a mean effective half-life of 33.4 hours and 46.2 hours in these groups, respectively. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The approximate plasma clearance of cyclobenzaprine is 0.7 L/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD 50 of cyclobenzaprine in mice and rats is 338 mg/kg and 425 mg/kg, respectively. Signs of overdose may develop rapidly after ingestion and commonly include significant drowsiness and tachycardia, with less common manifestations including tremor, agitation, ataxia, GI upset, and other CNS effects such as confusion and hallucinations. Potentially critical manifestations, though rare, include cardiac arrest or dysrhythmias, severe hypotension, seizures, and neuroleptic malignant syndrome. As the management of cyclobenzaprine overdose is complex and ever-changing, it is recommended that a poison control center be consulted prior to treatment. Typical management involves gastrointestinal decontamination, close cardiac monitoring, and monitoring for signs of CNS or respiratory depression. As cyclobenzaprine exists in relatively low concentrations in plasma, monitoring of drug plasma levels should not guide management and dialysis is likely of no value. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Amrix, Fexmid, Flexeril •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciclobenzaprina Cyclobenzaprine Cyclobenzaprinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cyclobenzaprine is a skeletal muscle relaxant that works on the brainstem to treat muscle spasms of local origin. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Cyclophosphamide interact?

•Drug A: Adalimumab •Drug B: Cyclophosphamide •Severity: MAJOR •Description: The metabolism of Cyclophosphamide can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cyclophosphamide is indicated for the treatment of malignant lymphomas, multiple myeloma, leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also indicated for the treatment of biopsy-proven minimal change nephrotic syndrome in pediatric patients. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, peak concentrations occur at one hour. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 30-50 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20% of cyclophosphamide is protein bound with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 3-12 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Total body clearance = 63 ± 7.6 L/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Procytox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (±)-2-(BIS(2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZAPHOSPHORINE 2-OXIDE MONOHYDRATE (RS)-Cyclophosphamide Ciclofosfamida Ciclofosfamide Cyclophosphamid Cyclophosphamide Cyclophosphamidum Cytophosphane •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cyclophosphamide is a nitrogen mustard used to treat lymphomas, myelomas, leukemia, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and breast carcinoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Cyclophosphamide interact? Information: •Drug A: Adalimumab •Drug B: Cyclophosphamide •Severity: MAJOR •Description: The metabolism of Cyclophosphamide can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cyclophosphamide is indicated for the treatment of malignant lymphomas, multiple myeloma, leukemias, mycosis fungoides (advanced disease), neuroblastoma (disseminated disease), adenocarcinoma of the ovary, retinoblastoma, and carcinoma of the breast. It is also indicated for the treatment of biopsy-proven minimal change nephrotic syndrome in pediatric patients. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cyclophosphamide is an antineoplastic in the class of alkylating agents and is used to treat various forms of cancer. Alkylating agents are so named because of their ability to add alkyl groups to many electronegative groups under conditions present in cells. They stop tumor growth by cross-linking guanine bases in DNA double-helix strands - directly attacking DNA. This makes the strands unable to uncoil and separate. As this is necessary in DNA replication, the cells can no longer divide. In addition, these drugs add methyl or other alkyl groups onto molecules where they do not belong which in turn inhibits their correct utilization by base pairing and causes a miscoding of DNA. Alkylating agents are cell cycle-nonspecific. Alkylating agents work by three different mechanisms all of which achieve the same end result - disruption of DNA function and cell death. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Alkylating agents work by three different mechanisms: 1) attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA, 2) DNA damage via the formation of cross-links (bonds between atoms in the DNA) which prevents DNA from being separated for synthesis or transcription, and 3) the induction of mispairing of the nucleotides leading to mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, peak concentrations occur at one hour. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 30-50 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 20% of cyclophosphamide is protein bound with no dose dependent changes. Some metabolites are protein bound to an extent greater than 60%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism and activation occurs at the liver. 75% of the drug is activated by cytochrome P450 isoforms, CYP2A6, 2B6, 3A4, 3A5, 2C9, 2C18, and 2C19. The CYP2B6 isoform is the enzyme with the highest 4-hydroxylase activity. Cyclophosphamide undergoes activation to eventually form active metabolites, phosphoramide mustard and acrolein. Cyclophosphamide appears to induce its own metabolism which results in an overall increase in clearance, increased formation of 4-hydroxyl metabolites, and shortened t1/2 values following repeated administration. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Cyclophosphamide is eliminated primarily in the form of metabolites. 10-20% is excreted unchanged in the urine and 4% is excreted in the bile following IV administration. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 3-12 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Total body clearance = 63 ± 7.6 L/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Adverse reactions reported most often include neutropenia, febrile neutropenia, fever, alopecia, nausea, vomiting, and diarrhea. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Procytox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (±)-2-(BIS(2-CHLOROETHYL)AMINO)TETRAHYDRO-2H-1,3,2-OXAZAPHOSPHORINE 2-OXIDE MONOHYDRATE (RS)-Cyclophosphamide Ciclofosfamida Ciclofosfamide Cyclophosphamid Cyclophosphamide Cyclophosphamidum Cytophosphane •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cyclophosphamide is a nitrogen mustard used to treat lymphomas, myelomas, leukemia, mycosis fungoides, neuroblastoma, ovarian adenocarcinoma, retinoblastoma, and breast carcinoma. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2A6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Cyclosporine interact?

•Drug A: Adalimumab •Drug B: Cyclosporine •Severity: MODERATE •Description: The serum concentration of Cyclosporine can be decreased when it is combined with Adalimumab. •Extended Description: Use of adalimumab leads to suppression of cytokines which can increase the production of Cytochrome P450 enzymes. As a result, concurrent use of adalimumab with drugs that utilize CYP450 enzymes for metabolism, such as cyclosporine, can lead to decreased concentration of those drugs. Conversely, discontinuation of adalimumab can lead to an increase in cyclosporine concentrations. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cyclosporine is approved for a variety of conditions. Firstly, it is approved for the prophylaxis of organ rejection in allogeneic kidney, liver, and heart transplants. It is also used to prevent bone marrow transplant rejection. For the above indications, cyclosporine can be used in conjunction with azathioprine and corticosteroids. Finally, cyclosporine can be used in patients who have chronic transplant rejection and have received previous immunosuppressive therapy and to prevent or treat graft-versus-host disease (GVHD). Secondly, cyclosporine is used for the treatment of patients with severe active rheumatoid arthritis (RA) when they no longer respond to methotrexate alone. It can be used for the treatment of adult non-immunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated. The ophthalmic solution of cyclosporine is indicated to increase tear production in patients suffering from keratoconjunctivitis sicca. In addition, cyclosporine is approved for the treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases which may include minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis. A cyclosporine ophthalmic emulsion is indicated in the treatment of vernal keratoconjunctivitis in adults and children. Off-label, cyclosporine is commonly used for the treatment of various autoimmune and inflammatory conditions such as atopic dermatitis, blistering disorders, ulcerative colitis, juvenile rheumatoid arthritis, uveitis, connective tissue diseases, as well as idiopathic thrombocytopenic purpura. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease. Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cyclosporine is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose. The C max of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily. A note on erratic absorption During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 50% of the administered dose is taken up by erythrocytes while about 34% is bound to lipoproteins. Prescribing information for Sandimmune states that 90% is mainly bound to lipoproteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies. The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Cyclosporin shows a linear clearance profile that ranges from 0.38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22.5 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD50 in rats is 1480 mg/kg and the TDLO in humans is 12 mg/kg. Overdose information In cases of overdose with oral cyclosporine, forced emesis and gastric lavage are recommended 2 hours after ingestion. There are little data available in the literature regarding overdoses with cyclosporine, but hepatotoxicity and nephrotoxicity may occur. One case report of an cyclosporine overdose due to medical error was made involving a 26 year old female and noted the occurrence of nausea, flushing, tremor, vertigo and vomiting, which resolved within about 1 day. Anorexia and a feeling of increased body girth were also experienced by this patient and resolved within about 2 weeks. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal, hemoperfusion are not effective techniques to remove cyclosporine from the body. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cequa, Gengraf, Neoral, Restasis, Sandimmune, Verkazia, Vevye •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciclosporin Ciclosporina Ciclosporine Ciclosporinum Cyclosporin Cyclosporin A Cyclosporine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cyclosporine is a steroid-sparing immunosuppressant used in organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis, and atopic dermatitis.

Use of adalimumab leads to suppression of cytokines which can increase the production of Cytochrome P450 enzymes. As a result, concurrent use of adalimumab with drugs that utilize CYP450 enzymes for metabolism, such as cyclosporine, can lead to decreased concentration of those drugs. Conversely, discontinuation of adalimumab can lead to an increase in cyclosporine concentrations. The severity of the interaction is moderate.

Question: Does Adalimumab and Cyclosporine interact? Information: •Drug A: Adalimumab •Drug B: Cyclosporine •Severity: MODERATE •Description: The serum concentration of Cyclosporine can be decreased when it is combined with Adalimumab. •Extended Description: Use of adalimumab leads to suppression of cytokines which can increase the production of Cytochrome P450 enzymes. As a result, concurrent use of adalimumab with drugs that utilize CYP450 enzymes for metabolism, such as cyclosporine, can lead to decreased concentration of those drugs. Conversely, discontinuation of adalimumab can lead to an increase in cyclosporine concentrations. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Cyclosporine is approved for a variety of conditions. Firstly, it is approved for the prophylaxis of organ rejection in allogeneic kidney, liver, and heart transplants. It is also used to prevent bone marrow transplant rejection. For the above indications, cyclosporine can be used in conjunction with azathioprine and corticosteroids. Finally, cyclosporine can be used in patients who have chronic transplant rejection and have received previous immunosuppressive therapy and to prevent or treat graft-versus-host disease (GVHD). Secondly, cyclosporine is used for the treatment of patients with severe active rheumatoid arthritis (RA) when they no longer respond to methotrexate alone. It can be used for the treatment of adult non-immunocompromised patients with severe, recalcitrant, plaque psoriasis that have failed to respond to at least one systemic therapy or when systemic therapies are not tolerated or contraindicated. The ophthalmic solution of cyclosporine is indicated to increase tear production in patients suffering from keratoconjunctivitis sicca. In addition, cyclosporine is approved for the treatment of steroid dependent and steroid-resistant nephrotic syndrome due to glomerular diseases which may include minimal change nephropathy, focal and segmental glomerulosclerosis or membranous glomerulonephritis. A cyclosporine ophthalmic emulsion is indicated in the treatment of vernal keratoconjunctivitis in adults and children. Off-label, cyclosporine is commonly used for the treatment of various autoimmune and inflammatory conditions such as atopic dermatitis, blistering disorders, ulcerative colitis, juvenile rheumatoid arthritis, uveitis, connective tissue diseases, as well as idiopathic thrombocytopenic purpura. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cyclosporine exerts potent immunosuppressive actions on T cells, thereby prolonging survival following organ and bone marrow transplants. This drug prevents and controls serious immune-mediated reactions including allograft rejection, graft versus host disease, and inflammatory autoimmune disease. Some notable effects of cyclosporine are hypertrichosis, gingival hyperplasia, and hyperlipidemia. There is also some debate about this drug causing nephrotoxicity. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cyclosporine is a calcineurin inhibitor that inhibits T cell activation. Its binding to the receptor cyclophilin-1 inside cells produces a complex known as cyclosporine-cyclophilin. This complex subsequently inhibits calcineurin, which in turn stops the dephosphorylation as well as the activation of the nuclear factor of activated T cells (NF-AT) that normally cause inflammatory reactions. NF-AT is a transcription factor that promotes the production of cytokines such as IL-2, IL-4, interferon-gamma and TNF-alpha, all of which are involved in the inflammatory process. Specifically, the inhibition of IL-2, which is necessary for T cell activation or proliferation, is believed to be responsible for cyclosporine's immunosuppressive actions. In addition to the above, the inhibition of NF-AT leads to lower levels of other factors associated with T helper cell function and thymocyte development. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absorption of cyclosporine occurs mainly in the intestine. Absorption of cyclosporine is highly variable with a peak bioavailability of 30% sometimes occurring 1-8 hours after administration with a second peak observed in certain patients. The absorption of cyclosporine from the GI tract has been found to be incomplete, likely due to first pass effects. Cmax in both the blood and plasma occurs at approximately 3.5 hours post-dose. The C max of a 0.1% cyclosporine ophthalmic emulsion is 0.67 ng/mL after instilling one drop four times daily. A note on erratic absorption During chronic administration, the absorption of Sandimmune Soft Gelatin Capsules and Oral Solution have been observed to be erratic, according to Novartis prescribing information. Those being administered the soft gelatin capsules or oral solution over the long term should be regularly monitored by testing cyclosporine blood concentrations and adjusting the dose accordingly. When compared with the other oral forms of Sandimmune, Neoral capsules and solution have a higher rate of absorption that results in a higher Tmax and a 59% higher Cmax with a 29 % higher bioavailability. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The distribution of cyclosporine in the blood consists of 33%-47% in plasma, 4%-9% in the lymphocytes, 5%-12% in the granulocytes, and 41%-58% in the erythrocytes. The reported volume of distribution of cyclosporine ranges from 4-8 L/kg. It concentrates mainly in leucocyte-rich tissues as well as tissues that contain high amounts of fat because it is highly lipophilic. Cyclosporine, in the eye drop formulation, crosses the blood-retinal barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 50% of the administered dose is taken up by erythrocytes while about 34% is bound to lipoproteins. Prescribing information for Sandimmune states that 90% is mainly bound to lipoproteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Cyclosporine is metabolized in the intestine and the liver by CYP450 enzymes, predominantly CYP3A4 with contributions from CYP3A5. The involvement of CYP3A7 is not clearly established. Cyclosporine undergoes several metabolic pathways and about 25 different metabolites have been identified. One of its main active metabolites, AM1, demonstrates only 10-20% activity when compared to the parent drug, according to some studies. The 3 primary metabolites are M1, M9, and M4N, which are produced from oxidation at the 1-beta, 9-gamma, and 4-N-demethylated positions, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After sulfate conjugation, cyclosporine remains in the bile where it is broken down to the original compound and then re-absorbed into the circulation. Cyclosporine excretion is primarily biliary with only 3-6% of the dose (including the parent drug and metabolites) excreted in the urine while 90% of the administered dose is eliminated in the bile. From the excreted proportion, under 1% of the dose is excreted as unchanged cyclosporine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of cyclosporine is biphasic and very variable on different conditions but it is reported in general to last 19 hours. Prescribing information also states a terminal half-life of approximately 19 hours, but with a range between 10 to 27 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Cyclosporin shows a linear clearance profile that ranges from 0.38 to 3 Lxh/kg, however, there is substantial inter- patient variability. A 250 mg dose of cyclosporine in the oral soft gelatin capsule of a lipid micro-emulsion formulation shows an approximate clearance of 22.5 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The oral LD50 in rats is 1480 mg/kg and the TDLO in humans is 12 mg/kg. Overdose information In cases of overdose with oral cyclosporine, forced emesis and gastric lavage are recommended 2 hours after ingestion. There are little data available in the literature regarding overdoses with cyclosporine, but hepatotoxicity and nephrotoxicity may occur. One case report of an cyclosporine overdose due to medical error was made involving a 26 year old female and noted the occurrence of nausea, flushing, tremor, vertigo and vomiting, which resolved within about 1 day. Anorexia and a feeling of increased body girth were also experienced by this patient and resolved within about 2 weeks. When overdose with cyclosporine is observed, it is important to consider that dialysis and charcoal, hemoperfusion are not effective techniques to remove cyclosporine from the body. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cequa, Gengraf, Neoral, Restasis, Sandimmune, Verkazia, Vevye •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ciclosporin Ciclosporina Ciclosporine Ciclosporinum Cyclosporin Cyclosporin A Cyclosporine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cyclosporine is a steroid-sparing immunosuppressant used in organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis, and atopic dermatitis. Output: Use of adalimumab leads to suppression of cytokines which can increase the production of Cytochrome P450 enzymes. As a result, concurrent use of adalimumab with drugs that utilize CYP450 enzymes for metabolism, such as cyclosporine, can lead to decreased concentration of those drugs. Conversely, discontinuation of adalimumab can lead to an increase in cyclosporine concentrations. The severity of the interaction is moderate.

Does Adalimumab and Cytarabine interact?

•Drug A: Adalimumab •Drug B: Cytarabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cytarabine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia. Cytarabine is indicated in combination with daunorubicin for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA. The latter mechanism is probably the most important. Cytotoxicity is highly specific for the S phase of the cell cycle. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cytarabine acts through direct DNA damage and incorporation into DNA. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Less than 20% of the orally administered dose is absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 13% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 10 minutes •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Cytarabine syndrome may develop - it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cytosar, Vyxeos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Citarabina Cytarabine Cytarabinum Cytosine arabinoside •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cytarabine is a pyrimidine nucleoside analogue used to treat acute non-lymphocytic leukemia, lymphocytic leukemia, and the blast phase of chronic myelocytic leukemia.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Cytarabine interact? Information: •Drug A: Adalimumab •Drug B: Cytarabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Cytarabine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of acute non-lymphocytic leukemia, acute lymphocytic leukemia and blast phase of chronic myelocytic leukemia. Cytarabine is indicated in combination with daunorubicin for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Cytarabine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute myelogenous leukemia and meningeal leukemia. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Cytarabine is metabolized intracellularly into its active triphosphate form (cytosine arabinoside triphosphate). This metabolite then damages DNA by multiple mechanisms, including the inhibition of alpha-DNA polymerase, inhibition of DNA repair through an effect on beta-DNA polymerase, and incorporation into DNA. The latter mechanism is probably the most important. Cytotoxicity is highly specific for the S phase of the cell cycle. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Cytarabine acts through direct DNA damage and incorporation into DNA. Cytarabine is cytotoxic to a wide variety of proliferating mammalian cells in culture. It exhibits cell phase specificity, primarily killing cells undergoing DNA synthesis (S-phase) and under certain conditions blocking the progression of cells from the G1 phase to the S-phase. Although the mechanism of action is not completely understood, it appears that cytarabine acts through the inhibition of DNA polymerase. A limited, but significant, incorporation of cytarabine into both DNA and RNA has also been reported. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Less than 20% of the orally administered dose is absorbed from the gastrointestinal tract. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 13% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The primary route of elimination of cytarabine is metabolism to the inactive compound ara-U, followed by urinary excretion of ara-U. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 10 minutes •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Cytarabine syndrome may develop - it is characterized by fever, myalgia, bone pain, occasionally chest pain, maculopapular rash, conjunctivitis, and malaise. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cytosar, Vyxeos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Citarabina Cytarabine Cytarabinum Cytosine arabinoside •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Cytarabine is a pyrimidine nucleoside analogue used to treat acute non-lymphocytic leukemia, lymphocytic leukemia, and the blast phase of chronic myelocytic leukemia. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Dabrafenib interact?

•Drug A: Adalimumab •Drug B: Dabrafenib •Severity: MAJOR •Description: The metabolism of Dabrafenib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): As monotherapy, dabrafenib is indicated to treat unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In combination with trametinib, dabrafenib is indicated to treat for: the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. Dabrafenib has limitations of use: it is neither indicated for treating patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition nor wild-type BRAF solid tumours. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and trametinib both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity. The melanoma approval for use with trametinib is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket. Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D. BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis. Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution (Vc/F) is 70.3 L. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dabrafenib is 99.7% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials. Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test. In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC). Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tafinlar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Dabrafenib interact? Information: •Drug A: Adalimumab •Drug B: Dabrafenib •Severity: MAJOR •Description: The metabolism of Dabrafenib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): As monotherapy, dabrafenib is indicated to treat unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. In combination with trametinib, dabrafenib is indicated to treat for: the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. the adjuvant treatment of melanoma with BRAF V600E or V600K mutations and involvement of lymph node(s), following complete resection. the treatment of metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation. the treatment of locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options. treatment of adult and pediatric patients six years and older with unresectable or metastatic solid tumours with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on the overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s). the treatment of pediatric patients one year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy. Dabrafenib has limitations of use: it is neither indicated for treating patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition nor wild-type BRAF solid tumours. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dabrafenib is a kinase inhibitor that is mainly used to target BRAF V600E mutation in multiple types of cancer. Although dabrafenib and trametinib both inhibit the RAS/RAF/MEK/ERK pathway, they inhibit different effectors of the pathway, thus increasing response rate and mitigating resistance without cumulative toxicity. The melanoma approval for use with trametinib is based on results from COMBI-AD, a Phase III study of 870 patients with Stage III BRAF V600E/K mutation-positive melanoma treated with dabrafenib + trametinib after complete surgical resection. Patients received doses of dabrafenib (150 mg BID) + trametinib (2 mg QD) combination (n = 438) or matching placebos (n = 432). After a median follow-up of 2.8 years, the primary endpoint of relapse-free survival (RFS) was met. In the case of thyroid cancer, Dabrafenib plus Trametinib is the first regimen demonstrated to have potent clinical activity in BRAF V600E–mutated anaplastic thyroid cancer and is well tolerated. These findings represent a meaningful therapeutic advance for this orphan disease. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dabrafenib is a competitive and selective BRAF inhibitor by binding to its ATP pocket. Although dabrafenib can inhibit wild-type BRAF, it has a higher affinity for mutant forms of BRAF, including BRAF V600E, BRAF V600K, and BRAF V600D. BRAF is a serine/threonine protein kinase and is involved in activating the RAS/RAF/MEK/ERK or MAPK pathway, a pathway that is implicated in cell cycle progression, cell proliferation, and arresting apoptosis. Therefore, constitutive active mutation of BRAF such as BRAF V600E is frequently observed in many types of cancer, including melanoma, lung cancer, and colon cancer. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, the median time to achieve peak plasma concentration (Tmax) is 2 hours. Mean absolute bioavailability of oral dabrafenib is 95%. Following a single dose, dabrafenib exposure (Cmax and AUC) increased in a dose-proportional manner across the dose range of 12 mg to 300 mg, but the increase was less than dose-proportional after repeat twice-daily dosing. After repeated twice-daily dosing of 150 mg, the mean accumulation ratio was 0.73, and the inter-subject variability (CV%) of AUC at steady-state was 38%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution (Vc/F) is 70.3 L. Distribution to the brain is restricted because dabrafenib is a substrate and undergoes efflux by P-glycoprotein and breast cancer resistance protein. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dabrafenib is 99.7% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of dabrafenib is primarily mediated by CYP2C8 and CYP3A4 to form hydroxy-dabrafenib. Hydroxy-dabrafenib is further oxidized via CYP3A4 to form carboxy-dabrafenib and subsequently excreted in bile and urine. Carboxy-dabrafenib is decarboxylated to form desmethyl-dabrafenib; desmethyl-dabrafenib may be reabsorbed from the gut. Desmethyl-dabrafenib is further metabolized by CYP3A4 to oxidative metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Fecal excretion is the major route of elimination accounting for 71% of radioactive dose while urinary excretion accounted for 23% of total radioactivity as metabolites only. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean terminal half-life of dabrafenib is 8 hours after oral administration. Hydroxy-dabrafenib's terminal half-life (10 hours) parallels that of dabrafenib while the carboxy- and desmethyl-dabrafenib metabolites exhibit longer half-lives (21 to 22 hours). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of dabrafenib is 17.0 L/h after single dosing and 34.4 L/h after 2 weeks of twice-daily dosing. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Carcinogenicity studies with dabrafenib have not been conducted. Dabrafenib increased the risk of cutaneous squamous cell carcinomas in patients in clinical trials. Dabrafenib was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay and was not clastogenic in an in vivo rat bone marrow micronucleus test. In a combined female fertility and embryo-fetal development study in rats, a reduction in fertility was noted at doses greater than or equal to 20 mg/kg/day (equivalent to the human exposure at the recommended dose based on AUC). A reduction in the number of ovarian corpora lutea was noted in pregnant females at 300 mg/kg/day (which is approximately three times the human exposure at the recommended dose based on AUC). Male fertility studies with dabrafenib have not been conducted; however, in repeat-dose studies, testicular degeneration/depletion was seen in rats and dogs at doses equivalent to and three times the human exposure at the recommended dose based on AUC, respectively. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tafinlar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dabrafenib is a kinase inhibitor used to treat patients with specific types of melanoma, non-small cell lung cancer, and thyroid cancer. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Dacarbazine interact?

•Drug A: Adalimumab •Drug B: Dacarbazine •Severity: MAJOR •Description: The metabolism of Dacarbazine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of metastatic malignant melanoma. In addition, dacarbazine is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other antineoplastic agents. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Erratic, slow and incomplete. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Less than 5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): LD 50 =350mg/kg (orally in mice) •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Biocarbazine Dacarbazin Dacarbazina Dacarbazine Dacarbazinum DTIC ICDMT •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dacarbazine is an antineoplastic agent used to treat malignant melanoma and Hodgkin's disease.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Dacarbazine interact? Information: •Drug A: Adalimumab •Drug B: Dacarbazine •Severity: MAJOR •Description: The metabolism of Dacarbazine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of metastatic malignant melanoma. In addition, dacarbazine is also indicated for Hodgkin's disease as a secondary-line therapy when used in combination with other antineoplastic agents. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dacarbazine is a synthetic analog of naturally occurring purine precursor 5-amino-1H-imidazole-4-carboxamide (AIC). After intravenous administration of dacarbazine, the volume of distribution exceeds total body water content suggesting localization in some body tissue, probably the liver. Its disappearance from the plasma is biphasic with initial half-life of 19 minutes and a terminal half-life of 5 hours. 1 In a patient with renal and hepatic dysfunctions, the half-lives were lengthened to 55 minutes and 7.2 hours. 1 The average cumulative excretion of unchanged DTIC in the urine is 40% of the injected dose in 6 hours. 1 DTIC is subject to renal tubular secretion rather than glomerular filtration. At therapeutic concentrations dacarbazine is not appreciably bound to human plasma protein. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The mechanism of action is not known, but appears to exert cytotoxic effects via its action as an alkylating agent. Other theories include DNA synthesis inhibition by its action as a purine analog, and interaction with SH groups. Dacarbazine is not cell cycle-phase specific. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Erratic, slow and incomplete. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Less than 5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Dacarbazine is subject to renal tubular secretion rather than glomerular filtration. In man, dacarbazine is extensively degraded. Besides unchanged dacarbazine, 5-aminoimidazole -4 carboxamide (AIC) is a major metabolite of dacarbazine excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 5 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): LD 50 =350mg/kg (orally in mice) •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Biocarbazine Dacarbazin Dacarbazina Dacarbazine Dacarbazinum DTIC ICDMT •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dacarbazine is an antineoplastic agent used to treat malignant melanoma and Hodgkin's disease. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Daclatasvir interact?

•Drug A: Adalimumab •Drug B: Daclatasvir •Severity: MODERATE •Description: The metabolism of Daclatasvir can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated for use with sofosbuvir, with or without ribavirin, for the treatment of chronic HCV genotype 1a/b or 3 infection. The dosing regimen of 60mg daclatasvir 60 mg with 400mg sofosbuvir once a day is recommended for both genontypes. Resistance: Reduced susceptibility to daclatasvir was associated with the polymorphisms at NS5A amino acid positions M28, Q30, L31, and Y93 in genotypes 1a, 1b, and 3a patients. NS5A Resistance Testing is recommended for HCV genotype 1a-infected patients with cirrhosis prior to the initiaition of the treatment, as the risk of resistance development is higher in genotype 1a patients. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daclatasvir is a direct-acting antiviral agent that targets the NS5A and causes a decrease in serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the critical functions of an NS5A protein in the replication complex. It is shown to cause downregulation of the hyperphosphorylation of NS5A. It does not appear to prolong the QT interval even when given at 3 times the maximum recommended dose. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): NS5A is a viral nonstructural phospoprotein that is part of a functional replication complex in charge of viral RNA genome amplification on endoplasmic reticulum membranes. It has the ability to bind to HCV RNA. It is shown to have two distinct functions in HCV RNA replication based on phosphorylated states. Maintaining the HCV replication complex is mediated by the cis-acting function of basally phosphorylated NS5A and the trans-acting function of hyperphosphorylated NS5A modulates HCV assembly and infectious particle formation. Daclatasvir is shown to disrupt hyperphosphorylated NS5A proteins thus interfere with the function of new HCV replication complexes. It is also reported that daclatasvir also blocks both intracellular viral RNA synthesis and virion assembly/secretion in vivo. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Studies demonstrated that peak plasma concentrations typically occurred within 2 hours after administration of multiple oral doses ranging from 1 - 100 mg once daily. Steady state is reached after approximately 4 days of once-daily daclatasvir administration. The absolute bioavailability of the tablet formulation is 67%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The approximate volume of distribution of daclatasvir is 47 L in patients who was orally administered 60 mg tablet followed by 100 µg [13C,15N]-daclatasvir intravenously. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Daclatasvir is highly protein bound (99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Daclastavir is a substrate of CYP3A enzymes where its metabolism is predominantly mediated by CYP3A4 isoform. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. High proportion of the drug in the plasma (greater than 97%) is in the unchanged form. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 88% of total dose of daclatasvir is eliminated into bile and feces in which 53% remains as unchanged form, while 6.6% of the total dose is eliminated primarily unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following multiple dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse effects experienced in patients undergoing daclatasvir and sofosbuvir therapy include headache, fatigue, nausea and diarrhea. Similar side effects are seen when ribavirin is added, in addition to rash, insomnia, anemia, dizziness and somnolence. There are postmarketing cases that link serious symptomatic bradycardia with Daklinza when used in conjunction with sofosbuvir and amiodarone. Coadministration of these three drugs is not recommended unless there are no other alternatives. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daclatasvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Daclatasvir interact? Information: •Drug A: Adalimumab •Drug B: Daclatasvir •Severity: MODERATE •Description: The metabolism of Daclatasvir can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Indicated for use with sofosbuvir, with or without ribavirin, for the treatment of chronic HCV genotype 1a/b or 3 infection. The dosing regimen of 60mg daclatasvir 60 mg with 400mg sofosbuvir once a day is recommended for both genontypes. Resistance: Reduced susceptibility to daclatasvir was associated with the polymorphisms at NS5A amino acid positions M28, Q30, L31, and Y93 in genotypes 1a, 1b, and 3a patients. NS5A Resistance Testing is recommended for HCV genotype 1a-infected patients with cirrhosis prior to the initiaition of the treatment, as the risk of resistance development is higher in genotype 1a patients. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daclatasvir is a direct-acting antiviral agent that targets the NS5A and causes a decrease in serum HCV RNA levels. It disrupts HCV replication by specifically inhibiting the critical functions of an NS5A protein in the replication complex. It is shown to cause downregulation of the hyperphosphorylation of NS5A. It does not appear to prolong the QT interval even when given at 3 times the maximum recommended dose. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): NS5A is a viral nonstructural phospoprotein that is part of a functional replication complex in charge of viral RNA genome amplification on endoplasmic reticulum membranes. It has the ability to bind to HCV RNA. It is shown to have two distinct functions in HCV RNA replication based on phosphorylated states. Maintaining the HCV replication complex is mediated by the cis-acting function of basally phosphorylated NS5A and the trans-acting function of hyperphosphorylated NS5A modulates HCV assembly and infectious particle formation. Daclatasvir is shown to disrupt hyperphosphorylated NS5A proteins thus interfere with the function of new HCV replication complexes. It is also reported that daclatasvir also blocks both intracellular viral RNA synthesis and virion assembly/secretion in vivo. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Studies demonstrated that peak plasma concentrations typically occurred within 2 hours after administration of multiple oral doses ranging from 1 - 100 mg once daily. Steady state is reached after approximately 4 days of once-daily daclatasvir administration. The absolute bioavailability of the tablet formulation is 67%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The approximate volume of distribution of daclatasvir is 47 L in patients who was orally administered 60 mg tablet followed by 100 µg [13C,15N]-daclatasvir intravenously. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Daclatasvir is highly protein bound (99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Daclastavir is a substrate of CYP3A enzymes where its metabolism is predominantly mediated by CYP3A4 isoform. Oxidative pathways included δ-oxidation of the pyrrolidine moiety, resulting in ring opening to an aminoaldehyde intermediate followed by an intramolecular reaction between the aldehyde and the proximal imidazole nitrogen atom. High proportion of the drug in the plasma (greater than 97%) is in the unchanged form. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 88% of total dose of daclatasvir is eliminated into bile and feces in which 53% remains as unchanged form, while 6.6% of the total dose is eliminated primarily unchanged in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Following multiple dose administration of daclatasvir in HCV-infected subjects, with doses ranging from 1 mg to 100 mg once daily, the terminal elimination half-life of daclatasvir ranged from approximately 12 to 15 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): In subjects who received daclatasvir 60 mg tablet orally followed by 100 µg radiolabeled daclatasvir intravenously, the total clearance was 4.2 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse effects experienced in patients undergoing daclatasvir and sofosbuvir therapy include headache, fatigue, nausea and diarrhea. Similar side effects are seen when ribavirin is added, in addition to rash, insomnia, anemia, dizziness and somnolence. There are postmarketing cases that link serious symptomatic bradycardia with Daklinza when used in conjunction with sofosbuvir and amiodarone. Coadministration of these three drugs is not recommended unless there are no other alternatives. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): No brand names available •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daclatasvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP3A5 substrates. The severity of the interaction is moderate.

Does Adalimumab and Dacomitinib interact?

•Drug A: Adalimumab •Drug B: Dacomitinib •Severity: MAJOR •Description: The metabolism of Dacomitinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Dacomitinib is indicated as the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as verified by an FDA-approved test. Lung cancer is the leading cause of cancer death and NSCLC accounts for 85% of lung cancer cases. From the cases of NSCLC, approximately 75% of the patients present a late diagnosis with metastatic and advanced disease which produces a survival rate of 5%. The presence of a mutation in EGFR accounts for more than the 60% of the NSCLC cases and the overexpression of EGFR is associated with frequent lymph node metastasis and poor chemosensitivity. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Preclinical data suggested that dacomitinib increases the inhibition of the epidermal growth factor receptor kinase domain as well as the activity in cell lines harboring resistance mutations such as T790M. This activity further produced a significant reduction of EGFR phosphorylation and cell viability. In these studies, non-small cell lymphoma cancer cell lines with L858R/T790M mutations where used and an IC50 of about 280 nmol/L was observed. In clinical trials with patients with advanced non-small cell lung carcinoma who progressed after chemotherapy, there was an objective response rate of 5% with a progression-free survival of 2.8 months and an overall survival of 9.5 months. As well, phase I/II studies showed positive dacomitinib activity despite prior failure with tyrosine kinase inhibitors. Phase III clinical trials (ARCHER 1050), done in patients suffering from advanced or metastatic non-small cell lung carcinoma with EGFR-activating mutations, reported a significant improvement in progression-free survival when compared with gefitinib. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors. The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L. The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus. Around 40% of cases show amplification of EGFR gene and 50% of the cases present the EGFRvIII mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Dacomitinib has shown a linear kinetics after single and multiple dose range studies. The absorption and distribution do not seem to be affected by food or the consumption of antacids. The peak plasma concentration after a dosage of 45 mg for 4 days is of 104 ng/ml. The reported AUC0-24h and tmax are of 2213 ng.h/mL and 6 hours, respectively. As well, following oral administration, the absolute oral bioavailability is 80%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of dacomitinib was reported to be of 2415 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dacomitinib is known to present a protein binding of 98%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes. After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265. This metabolite has been shown to be formed by an oxidative step by CYP2D6 and to a smaller extent by CYP2C9. The following steps of the metabolism are mainly mediated by CYP3A4 for the formation of smaller metabolites. From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): From the administered dose, 79% is recovered in feces, from which 20% represents the unmodified form of dacomitinib, and 3% is recovered in urine, from which <1% is represented by the unchanged form. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Dacomitinib is reported to have a very large half-life of 70 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric apparent clearance of dacomitinib is 27.06 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The maximum asymptomatic dose in rats was 50 mg/kg. In animal studies, dacomitinib was shown to induce embryo-fetal toxicity, as demonstrated by an increased incidence of a post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45mg human dose following administration in rats during the period of organogenesis. On the other hand, dacomitinib was showed to lack a mutagenic potential in a bacterial reverse mutation assay, in human lymphocyte chromosome aberration assay and in clastogenic or aneugenic in vivo rat bone marrow micronucleus assay. The dose-limiting and overdose toxicities include stomatitis, rash, palmar-plantar erythrodysesthesia syndrome, dehydration, paronychia, and diarrhea. From these findings, the maximum tolerated dose (defined by the dose in which the dose-limiting toxicities did not exceed 33%) is 45 mg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Vizimpro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dacomitinib Dacomitinibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dacomitinib is a medication used to treat non small cell lung cancer with EGFR exon 19 deletion of exon 21 L858R substitution.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Dacomitinib interact? Information: •Drug A: Adalimumab •Drug B: Dacomitinib •Severity: MAJOR •Description: The metabolism of Dacomitinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Dacomitinib is indicated as the first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations as verified by an FDA-approved test. Lung cancer is the leading cause of cancer death and NSCLC accounts for 85% of lung cancer cases. From the cases of NSCLC, approximately 75% of the patients present a late diagnosis with metastatic and advanced disease which produces a survival rate of 5%. The presence of a mutation in EGFR accounts for more than the 60% of the NSCLC cases and the overexpression of EGFR is associated with frequent lymph node metastasis and poor chemosensitivity. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Preclinical data suggested that dacomitinib increases the inhibition of the epidermal growth factor receptor kinase domain as well as the activity in cell lines harboring resistance mutations such as T790M. This activity further produced a significant reduction of EGFR phosphorylation and cell viability. In these studies, non-small cell lymphoma cancer cell lines with L858R/T790M mutations where used and an IC50 of about 280 nmol/L was observed. In clinical trials with patients with advanced non-small cell lung carcinoma who progressed after chemotherapy, there was an objective response rate of 5% with a progression-free survival of 2.8 months and an overall survival of 9.5 months. As well, phase I/II studies showed positive dacomitinib activity despite prior failure with tyrosine kinase inhibitors. Phase III clinical trials (ARCHER 1050), done in patients suffering from advanced or metastatic non-small cell lung carcinoma with EGFR-activating mutations, reported a significant improvement in progression-free survival when compared with gefitinib. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dacomitinib is an irreversible small molecule inhibitor of the activity of the human epidermal growth factor receptor (EGFR) family (EGFR/HER1, HER2, and HER4) tyrosine kinases. It achieves irreversible inhibition via covalent bonding to the cysteine residues in the catalytic domains of the HER receptors. The affinity of dacomitinib has been shown to have an IC50 of 6 nmol/L. The ErbB or epidermal growth factor (EGF) family plays a role in tumor growth, metastasis, and treatment resistance by activating downstream signal transduction pathways such as such as Ras-Raf-MAPK, PLCgamma-PKC-NFkB and PI3K/AKT through the tyrosine kinase-driven phosphorylation at the carboxy-terminus. Around 40% of cases show amplification of EGFR gene and 50% of the cases present the EGFRvIII mutation which represents a deletion that produces a continuous activation of the tyrosine kinase domain of the receptor. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Dacomitinib has shown a linear kinetics after single and multiple dose range studies. The absorption and distribution do not seem to be affected by food or the consumption of antacids. The peak plasma concentration after a dosage of 45 mg for 4 days is of 104 ng/ml. The reported AUC0-24h and tmax are of 2213 ng.h/mL and 6 hours, respectively. As well, following oral administration, the absolute oral bioavailability is 80%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The volume of distribution of dacomitinib was reported to be of 2415 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dacomitinib is known to present a protein binding of 98%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dacomitinib presents an oxidative and conjugative metabolism marked mainly by the activity of glutathione and cytochrome P450 enzymes. After metabolism, its major circulating metabolite is an O-desmethyl dacomitinib form named PF-05199265. This metabolite has been shown to be formed by an oxidative step by CYP2D6 and to a smaller extent by CYP2C9. The following steps of the metabolism are mainly mediated by CYP3A4 for the formation of smaller metabolites. From these metabolic studies, it was shown that dacomitinib inhibited strongly the activities of CYP2D6. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): From the administered dose, 79% is recovered in feces, from which 20% represents the unmodified form of dacomitinib, and 3% is recovered in urine, from which <1% is represented by the unchanged form. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Dacomitinib is reported to have a very large half-life of 70 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The geometric apparent clearance of dacomitinib is 27.06 L/h. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The maximum asymptomatic dose in rats was 50 mg/kg. In animal studies, dacomitinib was shown to induce embryo-fetal toxicity, as demonstrated by an increased incidence of a post-implantation loss and reduced fetal body weight at doses resulting in exposures near the exposure at the 45mg human dose following administration in rats during the period of organogenesis. On the other hand, dacomitinib was showed to lack a mutagenic potential in a bacterial reverse mutation assay, in human lymphocyte chromosome aberration assay and in clastogenic or aneugenic in vivo rat bone marrow micronucleus assay. The dose-limiting and overdose toxicities include stomatitis, rash, palmar-plantar erythrodysesthesia syndrome, dehydration, paronychia, and diarrhea. From these findings, the maximum tolerated dose (defined by the dose in which the dose-limiting toxicities did not exceed 33%) is 45 mg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Vizimpro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dacomitinib Dacomitinibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dacomitinib is a medication used to treat non small cell lung cancer with EGFR exon 19 deletion of exon 21 L858R substitution. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Dactinomycin interact?

•Drug A: Adalimumab •Drug B: Dactinomycin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Dactinomycin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma and metastatic, nonseminomatous testicular cancer as part of a combination chemotherapy and/or multi-modality treatment regimen •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Good evidence exists that this drug bind strongly, but reversibly, to DNA, interfering with synthesis of RNA (prevention of RNA polymerase elongation) and, consequently, with protein synthesis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): poorly absorbed from gastrointestinal tract •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): hepatic •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 36 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): hepatoxicity •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cosmegen •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3H-PHENOXAZINE-1,9-DICARBOXAMIDE, 2-AMINO-N,N'-BIS(HEXADECAHYDRO-6,13-DIISOPROPYL-2,5,9-TRIMETHYL-1,4,7,11,14-PENTAOXO-1H-PYRROLO(2,1-I)(1,4,7,10,13)OXATETRAAZACYCLOHEXADECIN-10-YL)-4,6-DIMETHYL-3-OXO- ActD Actinomycin C1 Actinomycin D ACTINOMYCIN I1 Actinomycin IV ACTINOMYCIN X1 ACTINOMYCIN-D ANA-conjugated dactinomycin nanoemulsion Dactinomicina Dactinomycin Dactinomycine Dactinomycinum DILACTONE ACTINOMYCIN D ACID Meractinomycin N,N'-((2-AMINO-4,6-DIMETHYL-3-OXO-3H-PHENOXAZINE-1,9-DIYL)-BIS(CARBONYLIMINO(2-HYDROXYPROPYLIDENE)CARBONYLIMINOISOBUTYLIDENECARBONYL-1,2-PYRROLIDINEDIYLCARBONYL(METHYLIMINO)METHYLENECARBONYL))BIS(N-METHYL-L-VALINE) DILACTONE ONCOSTATIN K •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dactinomycin is an actinomycin used to treat a wide variety of cancers.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Dactinomycin interact? Information: •Drug A: Adalimumab •Drug B: Dactinomycin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Dactinomycin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of Wilms' tumor, childhood rhabdomyosarcoma, Ewing's sarcoma and metastatic, nonseminomatous testicular cancer as part of a combination chemotherapy and/or multi-modality treatment regimen •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Generally, the actinomycins exert an inhibitory effect on gram-positive and gram-negative bacteria and on some fungi. However, the toxic properties of the actinomycins (including dactinomycin) in relation to antibacterial activity are such as to preclude their use as antibiotics in the treatment of infectious diseases. Because the actinomycins are cytotoxic, they have an antineoplastic effect which has been demonstrated in experimental animals with various types of tumor implant. This cytotoxic action is the basis for their use in the treatment of certain types of cancer. Dactinomycin is believed to produce its cytotoxic effects by binding DNA and inhibiting RNA synthesis. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Good evidence exists that this drug bind strongly, but reversibly, to DNA, interfering with synthesis of RNA (prevention of RNA polymerase elongation) and, consequently, with protein synthesis. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): poorly absorbed from gastrointestinal tract •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 5% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): hepatic •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 36 hours •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): hepatoxicity •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cosmegen •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 3H-PHENOXAZINE-1,9-DICARBOXAMIDE, 2-AMINO-N,N'-BIS(HEXADECAHYDRO-6,13-DIISOPROPYL-2,5,9-TRIMETHYL-1,4,7,11,14-PENTAOXO-1H-PYRROLO(2,1-I)(1,4,7,10,13)OXATETRAAZACYCLOHEXADECIN-10-YL)-4,6-DIMETHYL-3-OXO- ActD Actinomycin C1 Actinomycin D ACTINOMYCIN I1 Actinomycin IV ACTINOMYCIN X1 ACTINOMYCIN-D ANA-conjugated dactinomycin nanoemulsion Dactinomicina Dactinomycin Dactinomycine Dactinomycinum DILACTONE ACTINOMYCIN D ACID Meractinomycin N,N'-((2-AMINO-4,6-DIMETHYL-3-OXO-3H-PHENOXAZINE-1,9-DIYL)-BIS(CARBONYLIMINO(2-HYDROXYPROPYLIDENE)CARBONYLIMINOISOBUTYLIDENECARBONYL-1,2-PYRROLIDINEDIYLCARBONYL(METHYLIMINO)METHYLENECARBONYL))BIS(N-METHYL-L-VALINE) DILACTONE ONCOSTATIN K •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dactinomycin is an actinomycin used to treat a wide variety of cancers. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Daprodustat interact?

•Drug A: Adalimumab •Drug B: Daprodustat •Severity: MODERATE •Description: The metabolism of Daprodustat can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least four months. The US prescribing information for daprodustat indicates that the drug was not shown to improve quality of life, fatigue, or patient well-being. It is not advised to be used as a substitute for transfusion in patients requiring immediate correction of anemia. It is also not indicated in patients not on dialysis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daprodustat is Daprodustat increases endogenous erythropoietin in a dose-dependent manner within six to eight hours after administration. With repeated doses, peak increases in reticulocyte counts occurred in seven to 15 days, with subsequent increases in red blood cell production. New hemoglobin steady-state levels are reached several weeks (approximately four weeks in ESA-users and approximately 16-20 weeks in ESA-non-users) after initial administration. Daprodustat also increased serum transferrin and total iron binding capacity (TIBC) and decreased serum ferritin, transferrin saturation, and hepcidin when administered for 52 weeks in adults on dialysis with anemia due to CKD. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chronic kidney disease (CKD) is associated with several complications, including anemia. The development of anemia in patients with CKD is mostly due to the kidneys' inability to produce a sufficient amount of erythropoietin (EPO). Daprodustat is a potent reversible inhibitor of hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) 1, PH2 and PH3, with an IC 50 in the low nM range. By inhibiting HIF-PHDs, daprodustat promotes the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors. HIF-α translocates to the nucleus and binds to hypoxia response elements (HREs) on DNA to promote the production of EPO as well as proteins involved in iron uptake, mobilization, and transport. Ultimately, erythropoiesis is increased, iron transport is upregulated, and circulating Hb levels are elevated. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Daprodustat exposure generally increases in a dose-proportional manner over the range of therapeutic doses. Steady-state concentrations are achieved within 24 hours of dosing. Following oral administration, daprodustat is readily absorbed with a median time to peak concentration (T max ) in healthy subjects ranging from one to four hours. The absolute bioavailability of daprodustat is 65%. Administration of daprodustat with a high-fat or high-calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Daprodustat has an approximately equal distribution between plasma and blood cells (blood:plasma ratio of 1.23). Following intravenous dosing, the volume of distribution at steady-state in healthy subjects is 14.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, plasma protein binding of daprodustat is >99%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro, daprodustat is primarily metabolized by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%). Following oral or intravenous administration of radiolabeled daprodustat to healthy adults, approximately 40% of the total circulating radioactivity in plasma was daprodustat, and the remaining 60% was metabolites. The parent drug is the principal circulating component in plasma. Of the six metabolites of daprodustat that were characterized, the major metabolites were M2 (GSK2391220), M3 (GSK2506104), and M13 (GSK2531401), with each metabolite accounting for more than 10% of circulating radioactivity in plasma. In humans, each metabolite circulates primarily as a single stereoisomeric form. In vitro and non-clinical studies suggest that these identified metabolites have a comparable pharmacological activity to the parent drug; however, the extent of the pharmacological contribution of each metabolite is unknown. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Within seven days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% of the radioactivity was recovered in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the remaining fraction representing the unchanged parent drug. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal elimination half-life of daprodustat ranges from one to four hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Mean clearance from plasma was 18.9 L/h, which correlates to blood clearance of 15 L/h and equates to a hepatic extraction of approximately 18%. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Headache and gastrointestinal adverse reactions (e.g., nausea) may be seen with acute overdose with daprodustat. There is no specific antidote. Hemodialysis will not substantially remove daprodustat because it is highly protein bound. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Jesduvroq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Daprodustat •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daprodustat is a small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor used for the treatment of anemia in patients with chronic kidney disease.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Daprodustat interact? Information: •Drug A: Adalimumab •Drug B: Daprodustat •Severity: MODERATE •Description: The metabolism of Daprodustat can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Daprodustat is a hypoxia-inducible factor prolyl hydroxylase (HIF PH) inhibitor indicated for the treatment of anemia due to chronic kidney disease in adults who have been receiving dialysis for at least four months. The US prescribing information for daprodustat indicates that the drug was not shown to improve quality of life, fatigue, or patient well-being. It is not advised to be used as a substitute for transfusion in patients requiring immediate correction of anemia. It is also not indicated in patients not on dialysis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daprodustat is Daprodustat increases endogenous erythropoietin in a dose-dependent manner within six to eight hours after administration. With repeated doses, peak increases in reticulocyte counts occurred in seven to 15 days, with subsequent increases in red blood cell production. New hemoglobin steady-state levels are reached several weeks (approximately four weeks in ESA-users and approximately 16-20 weeks in ESA-non-users) after initial administration. Daprodustat also increased serum transferrin and total iron binding capacity (TIBC) and decreased serum ferritin, transferrin saturation, and hepcidin when administered for 52 weeks in adults on dialysis with anemia due to CKD. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Chronic kidney disease (CKD) is associated with several complications, including anemia. The development of anemia in patients with CKD is mostly due to the kidneys' inability to produce a sufficient amount of erythropoietin (EPO). Daprodustat is a potent reversible inhibitor of hypoxia-inducible factor (HIF)-prolyl hydroxylase (PH) 1, PH2 and PH3, with an IC 50 in the low nM range. By inhibiting HIF-PHDs, daprodustat promotes the stabilization and nuclear accumulation of HIF-1α and HIF-2α transcription factors. HIF-α translocates to the nucleus and binds to hypoxia response elements (HREs) on DNA to promote the production of EPO as well as proteins involved in iron uptake, mobilization, and transport. Ultimately, erythropoiesis is increased, iron transport is upregulated, and circulating Hb levels are elevated. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Daprodustat exposure generally increases in a dose-proportional manner over the range of therapeutic doses. Steady-state concentrations are achieved within 24 hours of dosing. Following oral administration, daprodustat is readily absorbed with a median time to peak concentration (T max ) in healthy subjects ranging from one to four hours. The absolute bioavailability of daprodustat is 65%. Administration of daprodustat with a high-fat or high-calorie meal did not significantly alter daprodustat exposure compared to administration in the fasted state. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Daprodustat has an approximately equal distribution between plasma and blood cells (blood:plasma ratio of 1.23). Following intravenous dosing, the volume of distribution at steady-state in healthy subjects is 14.3 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, plasma protein binding of daprodustat is >99%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro, daprodustat is primarily metabolized by CYP2C8 (95% contribution), with a minor contribution by CYP3A4 (5%). Following oral or intravenous administration of radiolabeled daprodustat to healthy adults, approximately 40% of the total circulating radioactivity in plasma was daprodustat, and the remaining 60% was metabolites. The parent drug is the principal circulating component in plasma. Of the six metabolites of daprodustat that were characterized, the major metabolites were M2 (GSK2391220), M3 (GSK2506104), and M13 (GSK2531401), with each metabolite accounting for more than 10% of circulating radioactivity in plasma. In humans, each metabolite circulates primarily as a single stereoisomeric form. In vitro and non-clinical studies suggest that these identified metabolites have a comparable pharmacological activity to the parent drug; however, the extent of the pharmacological contribution of each metabolite is unknown. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Within seven days of an oral dose of radiolabeled daprodustat, 74% of the radioactivity was recovered in the feces, and 21% of the radioactivity was recovered in the urine. Approximately 99.5% of the dose was excreted as oxidative metabolites, with the remaining fraction representing the unchanged parent drug. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal elimination half-life of daprodustat ranges from one to four hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Mean clearance from plasma was 18.9 L/h, which correlates to blood clearance of 15 L/h and equates to a hepatic extraction of approximately 18%. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Headache and gastrointestinal adverse reactions (e.g., nausea) may be seen with acute overdose with daprodustat. There is no specific antidote. Hemodialysis will not substantially remove daprodustat because it is highly protein bound. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Jesduvroq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Daprodustat •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daprodustat is a small-molecule hypoxia-inducible factor prolyl hydroxylase inhibitor used for the treatment of anemia in patients with chronic kidney disease. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C8 substrates. The severity of the interaction is moderate.

Does Adalimumab and Dapsone interact?

•Drug A: Adalimumab •Drug B: Dapsone •Severity: MODERATE •Description: The metabolism of Dapsone can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment and management of leprosy and dermatitis herpetiformis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dapsone is a sulfone with anti-inflammatory immunosuppressive properties as well as antibacterial and antibiotic properties. Dapsone is the principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy. As an anti-infective agent, it is also used for treating malaria and, recently, for Pneumocystic carinii pneumonia in AIDS patients. Dapsone is absorbed rapidly and nearly completely from the gastrointestinal tract. Dapsone is distributed throughout total body water and is present in all tissues. However, it tends to be retained in skin and muscle and especially in the liver and kidney: traces of the drug are present in these organs up to 3 weeks after therapy cessation. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dapsone acts against bacteria and protozoa in the same way as sulphonamides, that is by inhibiting the synthesis of dihydrofolic acid through competition with para-amino-benzoate for the active site of dihydropteroate synthetase. The anti-inflammatory action of the drug is unrelated to its antibacterial action and is still not fully understood. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bioavailability is 70 to 80% following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70 to 90% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, mostly CYP2E1-mediated. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Renal •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 28 hours (range 10-50 hours) •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aczone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): DADPS Dapsona Dapsone Dapsonum Diaphenylsulfone •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dapsone is a sulfone drug used to treat acne vulgaris, Hansen's disease, and dermatitis herpetiformis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Dapsone interact? Information: •Drug A: Adalimumab •Drug B: Dapsone •Severity: MODERATE •Description: The metabolism of Dapsone can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment and management of leprosy and dermatitis herpetiformis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dapsone is a sulfone with anti-inflammatory immunosuppressive properties as well as antibacterial and antibiotic properties. Dapsone is the principal drug in a multidrug regimen recommended by the World Health Organization for the treatment of leprosy. As an anti-infective agent, it is also used for treating malaria and, recently, for Pneumocystic carinii pneumonia in AIDS patients. Dapsone is absorbed rapidly and nearly completely from the gastrointestinal tract. Dapsone is distributed throughout total body water and is present in all tissues. However, it tends to be retained in skin and muscle and especially in the liver and kidney: traces of the drug are present in these organs up to 3 weeks after therapy cessation. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dapsone acts against bacteria and protozoa in the same way as sulphonamides, that is by inhibiting the synthesis of dihydrofolic acid through competition with para-amino-benzoate for the active site of dihydropteroate synthetase. The anti-inflammatory action of the drug is unrelated to its antibacterial action and is still not fully understood. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Bioavailability is 70 to 80% following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70 to 90% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic, mostly CYP2E1-mediated. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Renal •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 28 hours (range 10-50 hours) •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdosage might be expected to produce nasal congestion, syncope, or hallucinations. Measures to support blood pressure should be taken if necessary. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aczone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): DADPS Dapsona Dapsone Dapsonum Diaphenylsulfone •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dapsone is a sulfone drug used to treat acne vulgaris, Hansen's disease, and dermatitis herpetiformis. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Daratumumab interact?

•Drug A: Adalimumab •Drug B: Daratumumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Daratumumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Daratumumab is indicated as an intravenous injection alone or in combination with other medications for the treatment of multiple myeloma. It is available as a combination product with hyaluronidase for the treatment of adults with multiple myeloma as monotherapy or combination therapy and light chain amyloidosis in combination with other drugs. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daratumumab is a monoclonal antibody that targets and induces apoptosis in cells that highly express CD38, including multiple myeloma cells. It has a long duration of action as it is given every 1-4 weeks. Patients should be counselled regarding the risk of hypersensitivity, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interferences with cross-matching and red blood cell antibody screening. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): CD38 is a glycoprotein present on the surface of hematopoietic cells and is responsible for a number of cell signalling functions. Daratumumab is an immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that targets CD38. Cancers like multiple myeloma overexpress CD38, allowing daratumumab to have higher affinity for these cells. This binding allows daratumumab to induce apoptosis, antibody dependent cellular phagocytosis, and antibody and complement-dependent cytotoxicity. Antibody dependent cellular phagocytosis is mediated by the FC region of the antibody inducing phagocytes such as macrophages, antibody dependent cellular cytotoxicity is mediated by the FC region of the antibody inducing effector cells such as natural killer cells, and complement dependent cytotoxicity is mediated by the FC region of the antibody binding to and inducing complement protein activity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Subcutaneous daratumumab reaches a C max of 592µg/mL compared to intravenous daratumumab, which reaches a C max of 688µg/mL. The AUC of subcutaneous daratumumab is 4017µg/mL*day compared to intravenous daratumumab, which has an AUC of 4019µg/mL*day. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Daratumumab intravenous monotherapy has a volume of distribution of 4.7 ± 1.3L and the combination therapy has a volume of distribution of 4.4 ± 1.5L. Subcutaneous daratumumab has a volume of distribution of the central compartment of 5.2L and a volume of distribution of the peripheral compartment of 3.8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding protein binding of daratumumab in serum is not readily available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Monoclonal antibodies are expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Monoclonal antibodies are metabolized to amino acids used for synthesis of new proteins or are eliminated by the kidneys. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Intravenous daratumumab has a terminal half life of 18 ± 9 days. Subcutaneous daratumumab has a half life of 20 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Intravenous daratumumab has a clearance of 171.4 ± 95.3mL/day. Subcutaneous daratumumab has a clearance of 119mL/day. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding overdoses of daratumumab are not readily available. Patients should be treated with symptomatic and supportive measures. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Darzalex, Darzalex Faspro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daratumumab is a CD38-directed cytolytic antibody used alone or as an adjunct drug in the treatment of multiple myeloma and light chain amyloidosis.

Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Question: Does Adalimumab and Daratumumab interact? Information: •Drug A: Adalimumab •Drug B: Daratumumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Daratumumab. •Extended Description: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Daratumumab is indicated as an intravenous injection alone or in combination with other medications for the treatment of multiple myeloma. It is available as a combination product with hyaluronidase for the treatment of adults with multiple myeloma as monotherapy or combination therapy and light chain amyloidosis in combination with other drugs. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daratumumab is a monoclonal antibody that targets and induces apoptosis in cells that highly express CD38, including multiple myeloma cells. It has a long duration of action as it is given every 1-4 weeks. Patients should be counselled regarding the risk of hypersensitivity, neutropenia, thrombocytopenia, embryo-fetal toxicity, and interferences with cross-matching and red blood cell antibody screening. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): CD38 is a glycoprotein present on the surface of hematopoietic cells and is responsible for a number of cell signalling functions. Daratumumab is an immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that targets CD38. Cancers like multiple myeloma overexpress CD38, allowing daratumumab to have higher affinity for these cells. This binding allows daratumumab to induce apoptosis, antibody dependent cellular phagocytosis, and antibody and complement-dependent cytotoxicity. Antibody dependent cellular phagocytosis is mediated by the FC region of the antibody inducing phagocytes such as macrophages, antibody dependent cellular cytotoxicity is mediated by the FC region of the antibody inducing effector cells such as natural killer cells, and complement dependent cytotoxicity is mediated by the FC region of the antibody binding to and inducing complement protein activity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Subcutaneous daratumumab reaches a C max of 592µg/mL compared to intravenous daratumumab, which reaches a C max of 688µg/mL. The AUC of subcutaneous daratumumab is 4017µg/mL*day compared to intravenous daratumumab, which has an AUC of 4019µg/mL*day. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Daratumumab intravenous monotherapy has a volume of distribution of 4.7 ± 1.3L and the combination therapy has a volume of distribution of 4.4 ± 1.5L. Subcutaneous daratumumab has a volume of distribution of the central compartment of 5.2L and a volume of distribution of the peripheral compartment of 3.8L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding protein binding of daratumumab in serum is not readily available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Monoclonal antibodies are expected to be metabolized to smaller proteins and amino acids by proteolytic enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Monoclonal antibodies are metabolized to amino acids used for synthesis of new proteins or are eliminated by the kidneys. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Intravenous daratumumab has a terminal half life of 18 ± 9 days. Subcutaneous daratumumab has a half life of 20 days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Intravenous daratumumab has a clearance of 171.4 ± 95.3mL/day. Subcutaneous daratumumab has a clearance of 119mL/day. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Data regarding overdoses of daratumumab are not readily available. Patients should be treated with symptomatic and supportive measures. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Darzalex, Darzalex Faspro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daratumumab is a CD38-directed cytolytic antibody used alone or as an adjunct drug in the treatment of multiple myeloma and light chain amyloidosis. Output: Biologic therapies carry a risk of immunogenicity which can produce a wide array of adverse effects the most serious of which include anaphylaxis and serum sickness-type reactions . Use of multiple immunoglobulin-based therapies may increase the risk of these immunological complications. A few studies suggest the use of multiple immunoglobulin agents is relatively safe and may be more effective than monotherapy for certain conditions . The severity of the interaction is minor.

Does Adalimumab and Darifenacin interact?

•Drug A: Adalimumab •Drug B: Darifenacin •Severity: MODERATE •Description: The metabolism of Darifenacin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Darifenacin is a competitive muscarinic receptor antagonist. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Darifenacin selectively antagonizes the muscarinic M3 receptor. M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The mean oral bioavailability at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 163 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 40 L/h [extensive metabolizers] 32 L/h [poor metabolizers] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdosage can potentially result in severe central anticholinergic effects. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Emselex, Enablex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Darifenacin Darifenacina Darifénacine Darifenacinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Darifenacin is an M3 muscarinic receptor blocker used to treat urinary incontinence.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Darifenacin interact? Information: •Drug A: Adalimumab •Drug B: Darifenacin •Severity: MODERATE •Description: The metabolism of Darifenacin can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency and frequency. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Darifenacin is a competitive muscarinic receptor antagonist. In vitro studies using human recombinant muscarinic receptor subtypes show that darifenacin has greater affinity for the M3 receptor than for the other known muscarinic receptors (9 and 12-fold greater affinity for M3 compared to M1 and M5, respectively, and 59-fold greater affinity for M3 compared to both M2 and M4). Muscarinic receptors play an important role in several major cholinergically mediated functions, including contractions of the urinary bladder smooth muscle and stimulation of salivary secretion. Adverse drug effects such as dry mouth, constipation and abnormal vision may be mediated through effects on M3 receptors in these organs. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Darifenacin selectively antagonizes the muscarinic M3 receptor. M3 receptors are involved in contraction of human bladder and gastrointestinal smooth muscle, saliva production, and iris sphincter function. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The mean oral bioavailability at steady state is estimated to be 15% and 19% for 7.5 mg and 15 mg tablets, respectively. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): 163 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Darifenacin is approximately 98% bound to plasma proteins (primarily to alpha-1-acid-glycoprotein). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Primarily mediated by the cytochrome P450 enzymes CYP2D6 and CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No route of elimination available •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The elimination half-life of darifenacin following chronic dosing is approximately 13-19 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 40 L/h [extensive metabolizers] 32 L/h [poor metabolizers] •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdosage can potentially result in severe central anticholinergic effects. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Emselex, Enablex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Darifenacin Darifenacina Darifénacine Darifenacinum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Darifenacin is an M3 muscarinic receptor blocker used to treat urinary incontinence. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Dasabuvir interact?

•Drug A: Adalimumab •Drug B: Dasabuvir •Severity: MODERATE •Description: The metabolism of Dasabuvir can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Dasabuvir, in combination with Ombitasvir, Paritaprevir, and Ritonavir (as Viekira Pak) is indicated for the treatment of patients with HCV genotype 1a with Ribavirin or genotype 1b without Ribavirin including those with compensated cirrhosis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dasabuvir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotype 1. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor. The EC50 values of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 7.7 nM and 1.8 nM, respectively. By binding to NS5b outside of the active site of the enzyme, dasabuvir induces a conformational change thereby preventing further elongation of the nascent viral genome. A limitation of binding outside of the active site is that these binding sites are poorly preserved across the viral genotypes. This results in a limited potential for cross-genotypic activity and increased potential for development of resistance. Dasabuvir is therefore limited to treating genotypes 1a and 1b, and must be used in combination with other antiviral products. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Dasabuvir reaches peak plasma concentration 4 hours after administration. The absolute bioavailability of Dasabuvir is 70%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Dasabuvir has a volume of distribution at steady state of 149 liters. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dasabuvir is greater than 99.5% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dasabuvir is predominantly metabolized by CYP2C8, and to a lesser extent by CYP3A. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Dasabuvir is mainly excreted in the feces (94.4%) with very little excreted in the urine (2%). 26.2% and 0.03% of the drug excreted in the feces and urine respectively was present as the parent compound suggesting metabolism as the major elimination pathway. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of elimination of dasabuvir is 5.5 to 6 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Clearance of Dasabuvir has not been determined. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse effects of Viekira Pak either in combination with or without Ribavirin were pruritus, nausea, insomnia, and asthenia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Exviera, Viekira Pak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dasabuvir •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dasabuvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Dasabuvir interact? Information: •Drug A: Adalimumab •Drug B: Dasabuvir •Severity: MODERATE •Description: The metabolism of Dasabuvir can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Dasabuvir, in combination with Ombitasvir, Paritaprevir, and Ritonavir (as Viekira Pak) is indicated for the treatment of patients with HCV genotype 1a with Ribavirin or genotype 1b without Ribavirin including those with compensated cirrhosis. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dasabuvir is classified as a direct-acting antiviral (DAA) and prevents viral replication in HCV genotype 1. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication of the viral genome. Based on drug resistance mapping studies of HCV genotypes 1a and 1b, dasabuvir targets the palm domain of the NS5B polymerase, and is therefore referred to as a non-nucleoside NS5B-palm polymerase inhibitor. The EC50 values of dasabuvir against genotype 1a-H77 and 1b-Con1 strains in HCV replicon cell culture assays were 7.7 nM and 1.8 nM, respectively. By binding to NS5b outside of the active site of the enzyme, dasabuvir induces a conformational change thereby preventing further elongation of the nascent viral genome. A limitation of binding outside of the active site is that these binding sites are poorly preserved across the viral genotypes. This results in a limited potential for cross-genotypic activity and increased potential for development of resistance. Dasabuvir is therefore limited to treating genotypes 1a and 1b, and must be used in combination with other antiviral products. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Dasabuvir reaches peak plasma concentration 4 hours after administration. The absolute bioavailability of Dasabuvir is 70%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Dasabuvir has a volume of distribution at steady state of 149 liters. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Dasabuvir is greater than 99.5% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Dasabuvir is predominantly metabolized by CYP2C8, and to a lesser extent by CYP3A. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Dasabuvir is mainly excreted in the feces (94.4%) with very little excreted in the urine (2%). 26.2% and 0.03% of the drug excreted in the feces and urine respectively was present as the parent compound suggesting metabolism as the major elimination pathway. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of elimination of dasabuvir is 5.5 to 6 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Clearance of Dasabuvir has not been determined. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The most common adverse effects of Viekira Pak either in combination with or without Ribavirin were pruritus, nausea, insomnia, and asthenia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Exviera, Viekira Pak •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Dasabuvir •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dasabuvir is a direct-acting antiviral agent used to treat specific hepatitis C virus (HCV) infections in combination with other antiviral agents. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Dasatinib interact?

•Drug A: Adalimumab •Drug B: Dasatinib •Severity: MAJOR •Description: The metabolism of Dasatinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Dasatinib is indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, as well as adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Dasatinib is also indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase or newly diagnosed Ph+ ALL in combination with chemotherapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dasatinib is an orally available small-molecule multikinase inhibitor. During clinical trials, less than 1% of patients treated with dasatinib had QTc prolongation as an adverse reaction, and 1% experienced a QTcF higher than 500 ms. The use of dasatinib is also associated with myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, severe dermatologic reactions, tumor lysis syndrome and hepatotoxicity. It may also cause embryo-fetal toxicity and lead to adverse reactions associated with bone growth and development in pediatric patients. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dasatinib is a tyrosine kinase inhibitor with several targets. At nanomolar concentrations, it inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. In patients with chronic myeloid leukemia (CML), the tyrosine kinase activity of BCR-ABL is deregulated, leading to the growth, proliferation and survival of cancerous hematopoietic cells. Dasatinib binds to the active and inactive conformation of the ABL kinase domain with a higher affinity than imatinib. In chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL, dasatinib inhibits cell growth. Also, dasatinib has in vitro activity against leukemic cell lines that are either sensitive or resistant to imatinib. It has been suggested that dasatinib is able to overcome imatinib resistance caused by BCR-ABL kinase domain mutations because it does not require interaction with some of the residues involved in those mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Dasatinib has a dose-proportional pharmacokinetic profile and a linear elimination between 15 mg/day (0.15 times the lowest approved recommended dose) and 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg once a day, dasatinib has a C max and AUC of 82.2 ng/mL and 397 ng/mL*hr, respectively. In healthy adult subjects given dasatinib as dispersed tablets in juice, the adjusted geometric mean ratio compared to intact tablets was 0.97 for C max, and 0.84 for AUC. The T max of dasatinib is between 0.5 and 6 hours following oral administration. Following a single dose of 100 mg, a high-fat meal increases the AUC of dasatinib by 14%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Dasatinib has an apparent volume of distribution of 2505 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of dasatinib to human plasma proteins is approximately 96%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In humans, dasatinib is mainly metabolized by CYP3A4, although flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites. Five pharmacologically active dasatinib metabolites have been identified: M4, M5, M6, M20 and M24. M4, M20, and M24 are mainly generated by CYP3A4, M5 is generated by FMO3, and M6 is generated by a cytosolic oxidoreductase. M4 is equipotent to dasatinib and represents approximately 5% of the AUC. However, it is unlikely to play a major role in the observed pharmacology of dasatinib. M5 and M6 are more than 10 times less active than dasatinib and are considered minor circulating metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Dasatinib is mainly eliminated via feces. Within 10 days, 4% of dasatinib is recovered in urine, while 85% is recovered in feces. Approximately 0.1% and 19% of the administered dasatinib dose was recovered unchanged in urine and feces, respectively, and the rest was recovered as metabolites. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life of dasatinib is 3-5 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of dasatinib does not vary over time. Dasatinib has an apparent oral clearance of 363.8 L/hr. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdose cases with dasatinib occurred in isolated cases during clinical studies. Patients that received 280 mg of dasatinib per day for 1 week developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression, patients that ingest more than the recommended dosage should be monitored closely for myelosuppression and receive appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. In rodents, ventricular necrosis and valvular/ventricular/atrial hemorrhage were detected at single doses higher than or equal to 100 mg/kg (600 mg/m ). In monkeys receiving single doses higher than or equal to 10 mg/kg (120 mg/m ), there was a tendency for increased systolic and diastolic blood pressure. In rats, the oral LD 50 of dasatinib is 50-100 mg/kg, and in monkeys, it is 25-45 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Sprycel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Anh. dasatinib BMS dasatinib Dasatinib Dasatinib (anh.) Dasatinibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dasatinib is a tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Dasatinib interact? Information: •Drug A: Adalimumab •Drug B: Dasatinib •Severity: MAJOR •Description: The metabolism of Dasatinib can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Dasatinib is indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase, as well as adults with chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib, and adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Dasatinib is also indicated for the treatment of pediatric patients 1 year of age and older with Ph+ CML in chronic phase or newly diagnosed Ph+ ALL in combination with chemotherapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Dasatinib is an orally available small-molecule multikinase inhibitor. During clinical trials, less than 1% of patients treated with dasatinib had QTc prolongation as an adverse reaction, and 1% experienced a QTcF higher than 500 ms. The use of dasatinib is also associated with myelosuppression, bleeding-related events, fluid retention, cardiovascular toxicity, pulmonary arterial hypertension, severe dermatologic reactions, tumor lysis syndrome and hepatotoxicity. It may also cause embryo-fetal toxicity and lead to adverse reactions associated with bone growth and development in pediatric patients. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Dasatinib is a tyrosine kinase inhibitor with several targets. At nanomolar concentrations, it inhibits BCR-ABL, SRC family (SRC, LCK, YES, FYN), c-KIT, EPHA2, and PDGFRβ. In patients with chronic myeloid leukemia (CML), the tyrosine kinase activity of BCR-ABL is deregulated, leading to the growth, proliferation and survival of cancerous hematopoietic cells. Dasatinib binds to the active and inactive conformation of the ABL kinase domain with a higher affinity than imatinib. In chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL) cell lines overexpressing BCR-ABL, dasatinib inhibits cell growth. Also, dasatinib has in vitro activity against leukemic cell lines that are either sensitive or resistant to imatinib. It has been suggested that dasatinib is able to overcome imatinib resistance caused by BCR-ABL kinase domain mutations because it does not require interaction with some of the residues involved in those mutations. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Dasatinib has a dose-proportional pharmacokinetic profile and a linear elimination between 15 mg/day (0.15 times the lowest approved recommended dose) and 240 mg/day (1.7 times the highest approved recommended dose). At 100 mg once a day, dasatinib has a C max and AUC of 82.2 ng/mL and 397 ng/mL*hr, respectively. In healthy adult subjects given dasatinib as dispersed tablets in juice, the adjusted geometric mean ratio compared to intact tablets was 0.97 for C max, and 0.84 for AUC. The T max of dasatinib is between 0.5 and 6 hours following oral administration. Following a single dose of 100 mg, a high-fat meal increases the AUC of dasatinib by 14%. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Dasatinib has an apparent volume of distribution of 2505 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro, the binding of dasatinib to human plasma proteins is approximately 96%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In humans, dasatinib is mainly metabolized by CYP3A4, although flavin-containing monooxygenase 3 (FMO3) and uridine diphosphate-glucuronosyltransferase (UGT) enzymes are also involved in the formation of dasatinib metabolites. Five pharmacologically active dasatinib metabolites have been identified: M4, M5, M6, M20 and M24. M4, M20, and M24 are mainly generated by CYP3A4, M5 is generated by FMO3, and M6 is generated by a cytosolic oxidoreductase. M4 is equipotent to dasatinib and represents approximately 5% of the AUC. However, it is unlikely to play a major role in the observed pharmacology of dasatinib. M5 and M6 are more than 10 times less active than dasatinib and are considered minor circulating metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Dasatinib is mainly eliminated via feces. Within 10 days, 4% of dasatinib is recovered in urine, while 85% is recovered in feces. Approximately 0.1% and 19% of the administered dasatinib dose was recovered unchanged in urine and feces, respectively, and the rest was recovered as metabolites. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life of dasatinib is 3-5 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The clearance of dasatinib does not vary over time. Dasatinib has an apparent oral clearance of 363.8 L/hr. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Overdose cases with dasatinib occurred in isolated cases during clinical studies. Patients that received 280 mg of dasatinib per day for 1 week developed severe myelosuppression and bleeding. Since dasatinib is associated with severe myelosuppression, patients that ingest more than the recommended dosage should be monitored closely for myelosuppression and receive appropriate supportive treatment. Acute overdose in animals was associated with cardiotoxicity. In rodents, ventricular necrosis and valvular/ventricular/atrial hemorrhage were detected at single doses higher than or equal to 100 mg/kg (600 mg/m ). In monkeys receiving single doses higher than or equal to 10 mg/kg (120 mg/m ), there was a tendency for increased systolic and diastolic blood pressure. In rats, the oral LD 50 of dasatinib is 50-100 mg/kg, and in monkeys, it is 25-45 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Sprycel •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Anh. dasatinib BMS dasatinib Dasatinib Dasatinib (anh.) Dasatinibum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Dasatinib is a tyrosine kinase inhibitor used for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP1A2 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Daunorubicin interact?

•Drug A: Adalimumab •Drug B: Daunorubicin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Daunorubicin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Daunorubicin is indicated in combination with cytarabine for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daunorubicin is an anthracycline antibiotic and antineoplastic agent. It acts by inhibiting cellular reproduction through interference with DNA replication although it may contribute to the induction of cell death by increasing oxidative stress through the generation of reactive oxygen species and free radicals. As an antineoplastic agent, daunorubicin carries significant toxicities including cytopenias, hepatotoxicity, and extravasation reactions. Like other anthracyclines, daunorubicin also exhibits cardiotoxicity in proportion with the cumulative dose received over time. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Daunorubicin was found to have a tmax of 2 h and a cmax of 24.8 μg/mL after a 90 min infusion of the liposomal formulation at a dose of 44 mg/m. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Daunorubicin has a steady-state volume of distribution of 1.91 L/m reported with the liposomal formulation. The average volume of distribution reported for the liposomal formulation is 6.6 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Daunorubicin is eliminated hepatically. 40% of daunorubicin is excreted in the bile while 25% is excreted in an active form (daunorubicin or daunorubicinol) in the urine. In the liposomal formulation, only 9% of active molecules are excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Daunorubicin has been determined to have a terminal half-life of 18.5 h (+/- 4.9). Daunorubicinol, the primary active metabolite has been determined to have a terminal half-life of 26.7 h (+/- 12.8). The mean half-life of elimination of liposomal daunorubicin has been reported to be 22.1 h in pharmacokinetic studies and 31.5 h in official FDA labeling. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Daunorubicin has a clearance of 68.4 mL/h/m determined using the liposomal formulation. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cerubidine, Vyxeos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acetyladriamycin Daunomycin Daunorubicin Daunorubicin liposomal Daunorubicina Daunorubicine Daunorubicinum Leukaemomycin C Rubidomycin •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daunorubicin is an anthracycline aminoglycoside used to induce remission of nonlymphocytic leukemia and acute lymphocytic leukemia.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Daunorubicin interact? Information: •Drug A: Adalimumab •Drug B: Daunorubicin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Daunorubicin. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Daunorubicin is indicated in combination with cytarabine for the treatment of newly-diagnosed therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC) in adults and pediatric patients 1 year and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Daunorubicin is an anthracycline antibiotic and antineoplastic agent. It acts by inhibiting cellular reproduction through interference with DNA replication although it may contribute to the induction of cell death by increasing oxidative stress through the generation of reactive oxygen species and free radicals. As an antineoplastic agent, daunorubicin carries significant toxicities including cytopenias, hepatotoxicity, and extravasation reactions. Like other anthracyclines, daunorubicin also exhibits cardiotoxicity in proportion with the cumulative dose received over time. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Daunorubicin has antimitotic and cytotoxic activity through a number of proposed mechanisms of action: Daunorubicin forms complexes with DNA by intercalation between base pairs, and it inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex, preventing the religation portion of the ligation-religation reaction that topoisomerase II catalyzes. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Daunorubicin was found to have a tmax of 2 h and a cmax of 24.8 μg/mL after a 90 min infusion of the liposomal formulation at a dose of 44 mg/m. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Daunorubicin has a steady-state volume of distribution of 1.91 L/m reported with the liposomal formulation. The average volume of distribution reported for the liposomal formulation is 6.6 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No metabolism available •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Daunorubicin is eliminated hepatically. 40% of daunorubicin is excreted in the bile while 25% is excreted in an active form (daunorubicin or daunorubicinol) in the urine. In the liposomal formulation, only 9% of active molecules are excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Daunorubicin has been determined to have a terminal half-life of 18.5 h (+/- 4.9). Daunorubicinol, the primary active metabolite has been determined to have a terminal half-life of 26.7 h (+/- 12.8). The mean half-life of elimination of liposomal daunorubicin has been reported to be 22.1 h in pharmacokinetic studies and 31.5 h in official FDA labeling. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Daunorubicin has a clearance of 68.4 mL/h/m determined using the liposomal formulation. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cerubidine, Vyxeos •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acetyladriamycin Daunomycin Daunorubicin Daunorubicin liposomal Daunorubicina Daunorubicine Daunorubicinum Leukaemomycin C Rubidomycin •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Daunorubicin is an anthracycline aminoglycoside used to induce remission of nonlymphocytic leukemia and acute lymphocytic leukemia. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Decitabine interact?

•Drug A: Adalimumab •Drug B: Decitabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Decitabine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Decitabine is indicated for the treatment of patients with myelodysplastic syndromes (MDS) including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), as well as for MDS scored as belonging to the intermediate-1, intermediate-2, or high-risk group in the International Prognostic Scoring System. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Decitabine is a prodrug analogue of the natural nucleotide 2’-deoxycytidine, which, upon being phosphorylated intracellularly, is incorporated into DNA and exerts numerous effects on gene expression. The use of decitabine is associated with neutropenia and thrombocytopenia. In addition, decitabine can cause fetal harm in pregnant women; effective contraception and avoidance of pregnancy are recommended during treatment with decitabine. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (sAML). Included in the over 45 genes commonly mutated in MDS patients are those involved in DNA methylation and histone modification, and it is well-established that alteration of the epigenetic landscape is a feature of myeloid leukemias. Decitabine is considered a prodrug, as it requires transport into cells and subsequent phosphorylation by distinct kinases to generate the active molecule 5-aza-2'-deoxycytidine-triphosphate, which is incorporated by DNA polymerase during DNA replication. Once incorporated into DNA, decitabine is recognized as a substrate by DNA methyltransferase enzymes (DNMTs), specifically DNMT1, but due to the presence of an N5 rather than C5 atom, traps the DNMT through the irreversible formation of a covalent bond. At low concentrations, this mode of action depletes DNMTs and results in global DNA hypomethylation while at high concentrations, it additionally results in double-strand breaks and cell death. The general hypothesis regarding decitabine's therapeutic efficacy is that the global hypomethylation it induces results in the expression of previously silent tumour suppressor genes. However, there are other putative mechanisms also related to this change in DNA methylation, including indirect alteration of transcription through effects on transcription factors, indirectly altering histone modifications and chromatin structure, and activating pathways involved in DNA damage response. The overall effect of decitabine is a decrease in neoplastic cell proliferation and an increase in the expression of tumour suppressor genes. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Decitabine administered intravenously at 15 mg/m for three hours every eight hours over three days resulted in a C max of 73.8 ng/mL (66% coefficient of variation, CV), an AUC 0-∞ of 163 ng*h/mL (62% CV), and a cumulative AUC of 1332 ng*h/mL (95% CI of 1010-1730). Similarly, decitabine at 20 mg/m for one hour once daily over five days resulted in a C max of 147 ng/mL (49% CV), an AUC 0-∞ of 115 ng*h/mL (43% CV), and a cumulative AUC of 570 ng*h/mL (95% CI of 470-700). •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Decitabine as an apparent volume of distribution of 4.59 ± 1.42 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Decitabine exhibits negligible (< 1%) plasma protein binding. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Decitabine is phosphorylated inside cells by the sequential action of deoxycytidine kinase, nucleotide monophosphate kinase, and nucleotide diphosphate kinase, prior to being incorporated into newly synthesized DNA by DNA polymerase. Decitabine not incorporated into cellular DNA undergoes deamination by cytidine deaminase followed by additional degradation prior to excretion. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Less than 1% of administered decitabine is excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Decitabine has a half-life of 0.62 hours (49% CV) when administered intravenously at 15 mg/m for three hours every eight hours over three days, and a half-life of 0.54 hours (43% CV) at 20 mg/m for one hour once daily over five days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Decitabine has a clearance of 125 L/hr/m (53% CV) when administered intravenously at 15 mg/m for three hours every eight hours over three days, and a clearance of 210 L/hr/m (47% CV) at 20 mg/m for one hour once daily over five days. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Decitabine has demonstrated mutagenic potential in L5178Y mouse lymphoma cells and an Escherichia coil lac-I transgene within the colonic DNA of mice. Decitabine treatment increased chromosomal rearrangements in fruit fly larvae. In mouse models, decitabine exposure in utero (approximately 7% of the recommended daily dose) resulted in decreased weight and decreased male fertility. Adult male mice administered with between 0.3 and 1% of the recommended daily dose of decitabine three times a week for seven weeks had smaller testes with abnormal histology, decreased sperm count, and decreased fertility. There is no known antidote for decitabine overdose. Patients experiencing an overdose are at an increased risk of severe adverse effects such as myelosuppression, including prolonged and severe neutropenia and thrombocytopenia. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dacogen, Inqovi 5 Tablet Pack •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-azadeoxycytidine Decitabina Decitabine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Decitabine is a chemotherapeutic pyrimidine nucleoside analogue used for the treatment of myelodysplastic syndromes (MDS) by inducing DNA hypomethylation and corresponding alterations in gene expression.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Decitabine interact? Information: •Drug A: Adalimumab •Drug B: Decitabine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Decitabine. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Decitabine is indicated for the treatment of patients with myelodysplastic syndromes (MDS) including all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia), as well as for MDS scored as belonging to the intermediate-1, intermediate-2, or high-risk group in the International Prognostic Scoring System. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Decitabine is a prodrug analogue of the natural nucleotide 2’-deoxycytidine, which, upon being phosphorylated intracellularly, is incorporated into DNA and exerts numerous effects on gene expression. The use of decitabine is associated with neutropenia and thrombocytopenia. In addition, decitabine can cause fetal harm in pregnant women; effective contraception and avoidance of pregnancy are recommended during treatment with decitabine. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Myelodysplastic syndromes (MDS) are a group of hematopoietic neoplasms that manifest in peripheral cytopenias and may eventually progress to secondary acute myeloid leukemia (sAML). Included in the over 45 genes commonly mutated in MDS patients are those involved in DNA methylation and histone modification, and it is well-established that alteration of the epigenetic landscape is a feature of myeloid leukemias. Decitabine is considered a prodrug, as it requires transport into cells and subsequent phosphorylation by distinct kinases to generate the active molecule 5-aza-2'-deoxycytidine-triphosphate, which is incorporated by DNA polymerase during DNA replication. Once incorporated into DNA, decitabine is recognized as a substrate by DNA methyltransferase enzymes (DNMTs), specifically DNMT1, but due to the presence of an N5 rather than C5 atom, traps the DNMT through the irreversible formation of a covalent bond. At low concentrations, this mode of action depletes DNMTs and results in global DNA hypomethylation while at high concentrations, it additionally results in double-strand breaks and cell death. The general hypothesis regarding decitabine's therapeutic efficacy is that the global hypomethylation it induces results in the expression of previously silent tumour suppressor genes. However, there are other putative mechanisms also related to this change in DNA methylation, including indirect alteration of transcription through effects on transcription factors, indirectly altering histone modifications and chromatin structure, and activating pathways involved in DNA damage response. The overall effect of decitabine is a decrease in neoplastic cell proliferation and an increase in the expression of tumour suppressor genes. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Decitabine administered intravenously at 15 mg/m for three hours every eight hours over three days resulted in a C max of 73.8 ng/mL (66% coefficient of variation, CV), an AUC 0-∞ of 163 ng*h/mL (62% CV), and a cumulative AUC of 1332 ng*h/mL (95% CI of 1010-1730). Similarly, decitabine at 20 mg/m for one hour once daily over five days resulted in a C max of 147 ng/mL (49% CV), an AUC 0-∞ of 115 ng*h/mL (43% CV), and a cumulative AUC of 570 ng*h/mL (95% CI of 470-700). •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): Decitabine as an apparent volume of distribution of 4.59 ± 1.42 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Decitabine exhibits negligible (< 1%) plasma protein binding. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Decitabine is phosphorylated inside cells by the sequential action of deoxycytidine kinase, nucleotide monophosphate kinase, and nucleotide diphosphate kinase, prior to being incorporated into newly synthesized DNA by DNA polymerase. Decitabine not incorporated into cellular DNA undergoes deamination by cytidine deaminase followed by additional degradation prior to excretion. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Less than 1% of administered decitabine is excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): Decitabine has a half-life of 0.62 hours (49% CV) when administered intravenously at 15 mg/m for three hours every eight hours over three days, and a half-life of 0.54 hours (43% CV) at 20 mg/m for one hour once daily over five days. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Decitabine has a clearance of 125 L/hr/m (53% CV) when administered intravenously at 15 mg/m for three hours every eight hours over three days, and a clearance of 210 L/hr/m (47% CV) at 20 mg/m for one hour once daily over five days. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Decitabine has demonstrated mutagenic potential in L5178Y mouse lymphoma cells and an Escherichia coil lac-I transgene within the colonic DNA of mice. Decitabine treatment increased chromosomal rearrangements in fruit fly larvae. In mouse models, decitabine exposure in utero (approximately 7% of the recommended daily dose) resulted in decreased weight and decreased male fertility. Adult male mice administered with between 0.3 and 1% of the recommended daily dose of decitabine three times a week for seven weeks had smaller testes with abnormal histology, decreased sperm count, and decreased fertility. There is no known antidote for decitabine overdose. Patients experiencing an overdose are at an increased risk of severe adverse effects such as myelosuppression, including prolonged and severe neutropenia and thrombocytopenia. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dacogen, Inqovi 5 Tablet Pack •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 5-azadeoxycytidine Decitabina Decitabine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Decitabine is a chemotherapeutic pyrimidine nucleoside analogue used for the treatment of myelodysplastic syndromes (MDS) by inducing DNA hypomethylation and corresponding alterations in gene expression. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Deflazacort interact?

•Drug A: Adalimumab •Drug B: Deflazacort •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Deflazacort. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Deflazacort is indicated for the treatment of Duchenne Muscular Dystrophy (DMD) in patients 2 years of age and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Deflazacort exerts anti-inflammatory activity in DMD, likely improving various symptoms, including muscle weakness and cardiorespiratory symptoms in addition to delaying their onset. This allows for an increased quality of life and prevents the necessity for surgical procedures, such as those for scoliosis, which is associated with DMD. Studies showed significant preservation of muscle mass in patients generally treated with 0.9 mg/kg/day of deflazacort compared to a control group. The following findings are based on clinical studies using deflazacort on a long term basis: Effects on muscle strength At age 16, individuals treated with long-term deflazacort had 63 ± 4% score in muscle strength compared to a mean muscle strength score of 31 ± 3% for control patients. Significant improvements in climbing stairs and rising from a supine position were also seen in patients taking deflazacort. Effects on ambulation Ambulation was significantly higher by 12 years of age and 18 years of age in patients taking deflazacort when compared with the control group. The control group showed a mean loss of ambulation of 2 years sooner than with deflazacort treatment. Effects on cardiac function Mean left ventricular ejection fraction (a measure of cardiac function) was higher in patients treated with deflazacort over the long term. Preservation of cardiac function was demonstrated by a mean difference in ejection fraction of about 7%, favoring study groups taking deflazacort over control groups. Effects on spinal alignment Children treated with deflazacort also significantly lowered the rate and severity of scoliosis and eliminated the need for scoliosis surgery after long-term treatment. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Deflazacort is a corticosteroid prodrug with an active metabolite, 21-deflazacort, which binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects on the body. The exact mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown but likely occurs via its anti-inflammatory activities. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Deflazacort is rapidly absorbed after oral administration with peak concentration occurring within 1-2 hours. One pharmacokinetic study determined an AUC (area under the curve) of 280 ng/ml · h. The bioavailability of both the oral suspension and tablet are similar. In clinical studies, coadministration of deflazacort crushed with food or applesauce did not affect absorption or bioavailability. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): One study determined the volume of distribution to be 204 ± 84 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of the active metabolite of deflazacort is approximately 40%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After oral ingestion, deflazacort is deacetylated at position 21 by plasma esterases, producing the active metabolite 21-deflazacort. 21-deflazacort is then further metabolized by CYP3A4 to inactive metabolite products. Deflazacort 21-OH metabolism is extensive. The metabolite of deflazacort-21-OH is deflazacort 6-beta-OH. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Urinary excretion is the major route of deflazacort elimination, accounting for about about 70% of the excreted dose. The remainder of the dose (about 30%) is excreted in the feces. Elimination is almost completed by 24 hours post-dose. 21-deflazacort makes up about 18% of the eliminated drug in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of deflazacort ranges from 1.1 to 1.9 h •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 114 ±27 L/h, according to one noncompartmental pharmacokinetic study. The clearance of corticosteroids is enhanced in hypothyroid patients and increased in patients with hyperthyroidism. Dosing adjustments may be considered according to thyroid status. A study of corticosteroid clearance was performed in patients with a creatinine clearance of 15 mL/min or less, and determined that the active metabolite of deflazacort, 21-deflazacort was similar to that in patients with normal renal clearance. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The LD50 for the oral dose is 5200 mg/kg (mouse); Oral TDLO (woman): 0.12 mg/kg A note on altered endocrine function and immunosuppression Deflazacort, as a steroid prodrug used over a long-term period, can cause hormone imbalance leading to diseases such as Cushing's Syndrome and hypothalamic-pituitary-adrenal axis suppression. It can also predispose to infection, as it promotes immunosuppression. It is important to monitor for hormonal imbalance and infection and provide necessary treatment if they occur. Mutagenicity/carcinogenicity Mutagenicity assays were negative in various laboratory and in vivo assays performed on rats. Chronic use in mice for 2 years in one study resulted in a higher rate of osteoma and osteosarcomas in mice receiving 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg of deflazacort daily. Use in pregnancy There are no sufficient data to support the administration of deflazacort during pregnancy. Corticosteroid drugs such as deflazacort should only be used during pregnancy only if the benefits of therapy outweigh the potential risks. Use in lactation Corticosteroids, when administered systemically, are excreted in the breastmilk. Exposure may lead to disturbances in bone development and growth and endocrine disturbances in the exposed infant. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Emflaza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Deflazacort is a corticosteroid used to treat Duchenne muscular dystrophy.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Deflazacort interact? Information: •Drug A: Adalimumab •Drug B: Deflazacort •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Deflazacort. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Deflazacort is indicated for the treatment of Duchenne Muscular Dystrophy (DMD) in patients 2 years of age and older. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Deflazacort exerts anti-inflammatory activity in DMD, likely improving various symptoms, including muscle weakness and cardiorespiratory symptoms in addition to delaying their onset. This allows for an increased quality of life and prevents the necessity for surgical procedures, such as those for scoliosis, which is associated with DMD. Studies showed significant preservation of muscle mass in patients generally treated with 0.9 mg/kg/day of deflazacort compared to a control group. The following findings are based on clinical studies using deflazacort on a long term basis: Effects on muscle strength At age 16, individuals treated with long-term deflazacort had 63 ± 4% score in muscle strength compared to a mean muscle strength score of 31 ± 3% for control patients. Significant improvements in climbing stairs and rising from a supine position were also seen in patients taking deflazacort. Effects on ambulation Ambulation was significantly higher by 12 years of age and 18 years of age in patients taking deflazacort when compared with the control group. The control group showed a mean loss of ambulation of 2 years sooner than with deflazacort treatment. Effects on cardiac function Mean left ventricular ejection fraction (a measure of cardiac function) was higher in patients treated with deflazacort over the long term. Preservation of cardiac function was demonstrated by a mean difference in ejection fraction of about 7%, favoring study groups taking deflazacort over control groups. Effects on spinal alignment Children treated with deflazacort also significantly lowered the rate and severity of scoliosis and eliminated the need for scoliosis surgery after long-term treatment. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Deflazacort is a corticosteroid prodrug with an active metabolite, 21-deflazacort, which binds to the glucocorticoid receptor to exert anti-inflammatory and immunosuppressive effects on the body. The exact mechanism by which deflazacort exerts its therapeutic effects in patients with DMD is unknown but likely occurs via its anti-inflammatory activities. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Deflazacort is rapidly absorbed after oral administration with peak concentration occurring within 1-2 hours. One pharmacokinetic study determined an AUC (area under the curve) of 280 ng/ml · h. The bioavailability of both the oral suspension and tablet are similar. In clinical studies, coadministration of deflazacort crushed with food or applesauce did not affect absorption or bioavailability. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): One study determined the volume of distribution to be 204 ± 84 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of the active metabolite of deflazacort is approximately 40%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After oral ingestion, deflazacort is deacetylated at position 21 by plasma esterases, producing the active metabolite 21-deflazacort. 21-deflazacort is then further metabolized by CYP3A4 to inactive metabolite products. Deflazacort 21-OH metabolism is extensive. The metabolite of deflazacort-21-OH is deflazacort 6-beta-OH. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Urinary excretion is the major route of deflazacort elimination, accounting for about about 70% of the excreted dose. The remainder of the dose (about 30%) is excreted in the feces. Elimination is almost completed by 24 hours post-dose. 21-deflazacort makes up about 18% of the eliminated drug in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of deflazacort ranges from 1.1 to 1.9 h •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): 114 ±27 L/h, according to one noncompartmental pharmacokinetic study. The clearance of corticosteroids is enhanced in hypothyroid patients and increased in patients with hyperthyroidism. Dosing adjustments may be considered according to thyroid status. A study of corticosteroid clearance was performed in patients with a creatinine clearance of 15 mL/min or less, and determined that the active metabolite of deflazacort, 21-deflazacort was similar to that in patients with normal renal clearance. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): The LD50 for the oral dose is 5200 mg/kg (mouse); Oral TDLO (woman): 0.12 mg/kg A note on altered endocrine function and immunosuppression Deflazacort, as a steroid prodrug used over a long-term period, can cause hormone imbalance leading to diseases such as Cushing's Syndrome and hypothalamic-pituitary-adrenal axis suppression. It can also predispose to infection, as it promotes immunosuppression. It is important to monitor for hormonal imbalance and infection and provide necessary treatment if they occur. Mutagenicity/carcinogenicity Mutagenicity assays were negative in various laboratory and in vivo assays performed on rats. Chronic use in mice for 2 years in one study resulted in a higher rate of osteoma and osteosarcomas in mice receiving 0.06, 0.12, 0.25, 0.50, or 1.0 mg/kg of deflazacort daily. Use in pregnancy There are no sufficient data to support the administration of deflazacort during pregnancy. Corticosteroid drugs such as deflazacort should only be used during pregnancy only if the benefits of therapy outweigh the potential risks. Use in lactation Corticosteroids, when administered systemically, are excreted in the breastmilk. Exposure may lead to disturbances in bone development and growth and endocrine disturbances in the exposed infant. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Emflaza •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Deflazacort is a corticosteroid used to treat Duchenne muscular dystrophy. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Denosumab interact?

•Drug A: Adalimumab •Drug B: Denosumab •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Denosumab is combined with Adalimumab. •Extended Description: The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone.1,2,3 •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Denosumab under the brand name Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture. It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab under the brand name Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In clinical studies, treatment with 60 mg of denosumab resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodelling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e., osteocalcin and procollagen type 1 N-terminal peptide [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months. In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients. In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (C max ) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (T max ) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL. No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months. Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) C max values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) T max values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (± 36.5) ng/mL across all subjects (n = 12). In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4 (± 20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The central volume of distribution and volume of distribution at steady-state were calculated to be 2.49 L/66 kg and 3.5-7 L respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No information is available on the protein binding of denosumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No information is available on the metabolism of denosumab. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): After C max, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No information is available on the clearance of denosumab. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth. In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term animal studies. Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Prolia, Xgeva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures.

The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone.1,2,3 The severity of the interaction is moderate.

Question: Does Adalimumab and Denosumab interact? Information: •Drug A: Adalimumab •Drug B: Denosumab •Severity: MODERATE •Description: The risk or severity of adverse effects can be increased when Denosumab is combined with Adalimumab. •Extended Description: The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone.1,2,3 •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Denosumab under the brand name Prolia is indicated as a treatment for osteoporosis in menopausal women or men and glucocorticoid-induced osteoporosis in men and women at high risk of fracture. It is also used to increase bone mass in men at high risk for fractures receiving androgen deprivation therapy for nonmetastatic prostate cancer or women at high risk for fractures receiving adjuvant aromatase inhibitor therapy for breast cancer. Denosumab under the brand name Xgeva is indicated to prevent skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors and to treat giant cell tumors of bone in adults and skeletally mature adolescents and hypercalcemia of malignancy refractory to bisphosphonate therapy. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): In clinical studies, treatment with 60 mg of denosumab resulted in a reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodelling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment. Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e., osteocalcin and procollagen type 1 N-terminal peptide [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months. In patients with breast cancer and bone metastases, the median reduction in urinary N-terminal telopeptide corrected for creatinine (uNTx/Cr) was 82% within 1 week following initiation of denosumab 120 mg administered subcutaneously. In Studies 20050136, 20050244, and 20050103, the median reduction in uNTx/Cr from baseline to Month 3 was approximately 80% in 2075 denosumab-treated patients. In a phase 3 study of patients with newly diagnosed multiple myeloma who received subcutaneous doses of denosumab 120 mg every 4 weeks (Q4W), median reductions in uNTx/Cr of approximately 75% were observed by week 5. Reductions in bone turnover markers were maintained, with median reductions of 74% to 79% for uNTx/Cr from weeks 9 to 49 of continued 120 mg Q4W dosing. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Denosumab is designed to target RANKL (RANK ligand), a protein that acts as the primary signal to promote bone removal/resorption. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg after fasting (at least for 12 hours), the mean maximum denosumab concentration (C max ) was 6.75 mcg/mL (standard deviation [SD] = 1.89 mcg/mL). The median time to maximum denosumab concentration (T max ) was 10 days (range: 3 to 21 days). The mean area-under-the-concentration-time curve up to 16 weeks (AUC0-16 weeks) of denosumab was 316 mcg⋅day/mL (SD = 101 mcg⋅day/mL. No accumulation or change in denosumab pharmacokinetics with time was observed upon multiple dosing of 60 mg subcutaneously administered once every 6 months. Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (± SD) C max values in the serum and seminal fluid samples were 6170 (± 2070) and 100 (± 81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) T max values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in the seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (± SD) seminal fluid concentration of 21.1 (± 36.5) ng/mL across all subjects (n = 12). In patients with newly diagnosed multiple myeloma who received 120 mg every 4 weeks, denosumab concentrations appear to reach a steady state by month 6. In patients with giant cell tumor of bone, after administration of subcutaneous doses of 120 mg once every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy, mean (± standard deviation) serum trough concentrations on Day 8, 15, and one month after the first dose were 19.0 (± 24.1), 31.6 (± 27.3), 36.4 (± 20.6) mcg/mL, respectively. Steady-state was achieved in 3 months after initiation of treatment with a mean serum trough concentration of 23.4 (± 12.1) mcg/mL. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The central volume of distribution and volume of distribution at steady-state were calculated to be 2.49 L/66 kg and 3.5-7 L respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): No information is available on the protein binding of denosumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): No information is available on the metabolism of denosumab. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As an antibody, denosumab is likely cleared by the reticuloendothelial system with minimal renal filtration and excretion. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): After C max, serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46). •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No information is available on the clearance of denosumab. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Denosumab is contraindicated for use in pregnant women because it may cause harm to a fetus. There are insufficient data with denosumab use in pregnant women to inform any drug-associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab throughout pregnancy at a dose 50-fold higher than the recommended human dose based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, and absent lymph nodes, abnormal bone growth, and decreased neonatal growth. In clinical trials, hypercalcemia has been reported in pediatric patients with osteogenesis imperfect treated with denosumab products, including Prolia. Some cases required hospitalization and were complicated by acute renal injury. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. The carcinogenic and genotoxic potential of denosumab has not been evaluated in long-term animal studies. Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Prolia, Xgeva •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): No synonyms listed •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Denosumab is a RANK ligand (RANKL) inhibitor used for the management of osteoporosis in patients at high risk for bone fractures. Output: The coadministration of denosumab with immunosuppressive agents poses a high risk of serious infection than with denosumab alone.1,2,3 The severity of the interaction is moderate.

Does Adalimumab and Desipramine interact?

•Drug A: Adalimumab •Drug B: Desipramine •Severity: MAJOR •Description: The metabolism of Desipramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 73-92% bound to plasma proteins •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 7-60+ hours; 70% eliminated renally •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Male mice: LD50 = 290 mg/kg, female rats: LD50 = 320 mg/kg. Antagonism of the histamine H 1 and α 1 receptors can lead to sedation and hypotension. Antimuscarinic activity confers anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of desipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Norpramin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Déméthylimipramine Desipramin Desipramina Desipramine Désipramine Desipraminum Desmethylimipramine Monodemethylimipramine Norimipramine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desipramine is a tricyclic antidepressant used in the treatment of depression.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Desipramine interact? Information: •Drug A: Adalimumab •Drug B: Desipramine •Severity: MAJOR •Description: The metabolism of Desipramine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For relief of symptoms in various depressive syndromes, especially endogenous depression. It has also been used to manage chronic peripheral neuropathic pain, as a second line agent for the management of anxiety disorders (e.g. panic disorder, generalized anxiety disorder), and as a second or third line agent in the ADHD management. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Desipramine, a secondary amine tricyclic antidepressant, is structurally related to both the skeletal muscle relaxant cyclobenzaprine and the thioxanthene antipsychotics such as thiothixene. It is the active metabolite of imipramine, a tertiary amine TCA. The acute effects of desipramine include inhibition of noradrenaline re-uptake at noradrenergic nerve endings and inhibition of serotonin (5-hydroxy tryptamine, 5HT) re-uptake at the serotoninergic nerve endings in the central nervous system. Desipramine exhibits greater noradrenergic re-uptake inhibition compared to the tertiary amine TCA imipramine. In addition to inhibiting neurotransmitter re-uptake, desipramine down-regulates beta-adrenergic receptors in the cerebral cortex and sensitizes serotonergic receptors with chronic use. The overall effect is increased serotonergic transmission. Antidepressant effects are typically observed 2 - 4 weeks following the onset of therapy though some patients may require up to 8 weeks of therapy prior to symptom improvement. Patients experiencing more severe depressive episodes may respond quicker than those with mild depressive symptoms. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Desipramine is a tricyclic antidepressant (TCA) that selectively blocks reuptake of norepinephrine (noradrenaline) from the neuronal synapse. It also inhibits serotonin reuptake, but to a lesser extent compared to tertiary amine TCAs such as imipramine. Inhibition of neurotransmitter reuptake increases stimulation of the post-synaptic neuron. Chronic use of desipramine also leads to down-regulation of beta-adrenergic receptors in the cerebral cortex and sensitization of serotonergic receptors. An overall increase in serotonergic transmission likely confers desipramine its antidepressant effects. Desipramine also possesses minor anticholinergic activity, through its affinity for muscarinic receptors. TCAs are believed to act by restoring normal levels of neurotransmitters via synaptic reuptake inhibition and by increasing serotonergic neurotransmission via serotonergic receptor sensitization in the central nervous system. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Desipramine hydrochloride is rapidly and almost completely absorbed from the gastrointestinal tract. It undergoes extensive first-pass metabolism. Peak plasma concentrations are attained 4 - 6 hours following oral administration. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 73-92% bound to plasma proteins •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Desipramine is extensively metabolized in the liver by CYP2D6 (major) and CYP1A2 (minor) to 2-hydroxydesipramine, an active metabolite. 2-hydroxydesipramine is thought to retain some amine reuptake inhibition and may possess cardiac depressant activity. The 2-hydroxylation metabolic pathway of desipramine is under genetic control. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): 7-60+ hours; 70% eliminated renally •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Male mice: LD50 = 290 mg/kg, female rats: LD50 = 320 mg/kg. Antagonism of the histamine H 1 and α 1 receptors can lead to sedation and hypotension. Antimuscarinic activity confers anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of desipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Norpramin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Déméthylimipramine Desipramin Desipramina Desipramine Désipramine Desipraminum Desmethylimipramine Monodemethylimipramine Norimipramine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desipramine is a tricyclic antidepressant used in the treatment of depression. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2D6 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Desogestrel interact?

•Drug A: Adalimumab •Drug B: Desogestrel •Severity: MODERATE •Description: The metabolism of Desogestrel can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Oral desogestrel is used in combination with ethinylestradiol as a contraceptive agent for the prevention of pregnancy. Desogestrel is part of the combined oral contraceptives that contain a mix of estrogen and progestin which inhibit ovulation. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The effects of desogestrel are divided on reproductive including modification of luteinizing hormone and follicle stimulating hormone, declines on the onset of menstruation, and increases the viscosity of the vaginal fluid; and on metabolic that includes increase insulin secretion and resistance, increased lipase activity, and increased fat deposition. The effect of desogestrel on the lipids has been studied extensively and the results are contradictory. Desogestrel main therapeutic effect due to its mechanism of action is known to be related to the inhibition of the ovulation in 97% of the cycles. This effect was proven in clinical trials in non-breastfeeding women from which the Pearl failure rate was reported to be of 0.17 per 100 women-years. This result indicated that desogestrel is more efficient when compared to other progestogen-only pills. All the therapeutic effect is produced by a transformation of the endometrium followed by an inhibition of the ovulation due to the suppression of other hormones. Desogestrel has been widely confirmed to be related to an increase in the risk of venous thromboembolism due to the driven increased in blood coagulation factors, leading to a pronounced prothrombotic state. However, the effects of desogestrel are known to not impact significantly the level of total cholesterol remaining in the range of change of 10% which allows it to be a molecule that presents a favorable lipid profile. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Desogestrel enters the cell passively and acts by binding selectively to the progesterone receptor and generating low androgenic activity. Its binding produces an effect like a transcription factor and thus, it produces modifications in the mRNA synthesis. The active metabolite of desogestrel, etonogestrel, presents a combination of high progestational activity with minimal intrinsic androgenicity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, desogestrel is rapidly absorbed and it reaches a peak concentration of 2 ng/ml after 1.5 hours. The bioavailability of desogestrel is reported to be in the range of 60-80% and the reported AUC is of 3000 ng.h/ml. Almost all the administered dose is modified to the active metabolite, etonogestrel. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of desogestrel is of 1.5 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The main metabolite of desogestrel is mainly found bound to albumin and sex-hormone binding globulin. Around 96-98% of the administered dose of desogestrel is found bound to plasma proteins from which 40-70% is found bound to sex-hormone binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Desogestrel is rapidly metabolized in the intestinal mucosa and by first-pass hepatic metabolism to form the major metabolite of desogestrel is etonogestrel which is the biologically active metabolite. This modification is described by the hydroxylation in C3 of the desogestrel molecule. Later, etonogestrel is metabolized following the normal pathways of steroid metabolism. On the other hand, due to the 11-methylene side chain, desogestrel cannot be metabolized to other progestins. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of desogestrel is found to be mainly renal corresponding to about 6 times the dose eliminated in the bile. The elimination of desogestrel is only done as the metabolites and not as the unchanged drug and about 85% of the administered dose can be excreted as metabolites after 6-8 days. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life of desogestrel is determined to be of 30 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The metabolic clearance rate of desogestrel is reported to be of about 2 ml/min/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Administration of large quantities of desogestrel has been shown to produce strong hormonal effects but to lack chronic toxicity. The reported LD50 in rats after oral administration of desogestrel is higher than 2000 mg/kg. Overdose hasn't reported serious effects but only symptoms of nausea and withdrawal of bleeding. Most reports haven't linked the administration of desogestrel with the increased risk of breast cancer. The increased risk has been reported to be related to the duration of use. However, several reports indicate a desogestrel-driven increased risk in cervical intra-epithelial neoplasia but the results are still not conclusive. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Apri 28 Day, Azurette 28 Day, Bekyree 28 Day, Caziant 28 Day, Cesia 28 Day, Cyred 28 Day, Emoquette, Enskyce 28 Day, Freya, Isibloom 28 Day, Juleber 28 Day, Kalliga, Kariva 28 Day, Linessa, Marvelon, Mircette 28 Day, Pimtrea Pack, Reclipsen, Simliya, Velivet 28 Day, Viorele 28 Day, Volnea 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desogestrel Désogestrel Desogestrelum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desogestrel is a synthetic progestin used in contraception, often in combination with ethinyl estradiol.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Desogestrel interact? Information: •Drug A: Adalimumab •Drug B: Desogestrel •Severity: MODERATE •Description: The metabolism of Desogestrel can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Oral desogestrel is used in combination with ethinylestradiol as a contraceptive agent for the prevention of pregnancy. Desogestrel is part of the combined oral contraceptives that contain a mix of estrogen and progestin which inhibit ovulation. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): The effects of desogestrel are divided on reproductive including modification of luteinizing hormone and follicle stimulating hormone, declines on the onset of menstruation, and increases the viscosity of the vaginal fluid; and on metabolic that includes increase insulin secretion and resistance, increased lipase activity, and increased fat deposition. The effect of desogestrel on the lipids has been studied extensively and the results are contradictory. Desogestrel main therapeutic effect due to its mechanism of action is known to be related to the inhibition of the ovulation in 97% of the cycles. This effect was proven in clinical trials in non-breastfeeding women from which the Pearl failure rate was reported to be of 0.17 per 100 women-years. This result indicated that desogestrel is more efficient when compared to other progestogen-only pills. All the therapeutic effect is produced by a transformation of the endometrium followed by an inhibition of the ovulation due to the suppression of other hormones. Desogestrel has been widely confirmed to be related to an increase in the risk of venous thromboembolism due to the driven increased in blood coagulation factors, leading to a pronounced prothrombotic state. However, the effects of desogestrel are known to not impact significantly the level of total cholesterol remaining in the range of change of 10% which allows it to be a molecule that presents a favorable lipid profile. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): Desogestrel enters the cell passively and acts by binding selectively to the progesterone receptor and generating low androgenic activity. Its binding produces an effect like a transcription factor and thus, it produces modifications in the mRNA synthesis. The active metabolite of desogestrel, etonogestrel, presents a combination of high progestational activity with minimal intrinsic androgenicity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): After oral administration, desogestrel is rapidly absorbed and it reaches a peak concentration of 2 ng/ml after 1.5 hours. The bioavailability of desogestrel is reported to be in the range of 60-80% and the reported AUC is of 3000 ng.h/ml. Almost all the administered dose is modified to the active metabolite, etonogestrel. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The apparent volume of distribution of desogestrel is of 1.5 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The main metabolite of desogestrel is mainly found bound to albumin and sex-hormone binding globulin. Around 96-98% of the administered dose of desogestrel is found bound to plasma proteins from which 40-70% is found bound to sex-hormone binding globulin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Desogestrel is rapidly metabolized in the intestinal mucosa and by first-pass hepatic metabolism to form the major metabolite of desogestrel is etonogestrel which is the biologically active metabolite. This modification is described by the hydroxylation in C3 of the desogestrel molecule. Later, etonogestrel is metabolized following the normal pathways of steroid metabolism. On the other hand, due to the 11-methylene side chain, desogestrel cannot be metabolized to other progestins. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of desogestrel is found to be mainly renal corresponding to about 6 times the dose eliminated in the bile. The elimination of desogestrel is only done as the metabolites and not as the unchanged drug and about 85% of the administered dose can be excreted as metabolites after 6-8 days. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The terminal half-life of desogestrel is determined to be of 30 hours. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): The metabolic clearance rate of desogestrel is reported to be of about 2 ml/min/kg. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Administration of large quantities of desogestrel has been shown to produce strong hormonal effects but to lack chronic toxicity. The reported LD50 in rats after oral administration of desogestrel is higher than 2000 mg/kg. Overdose hasn't reported serious effects but only symptoms of nausea and withdrawal of bleeding. Most reports haven't linked the administration of desogestrel with the increased risk of breast cancer. The increased risk has been reported to be related to the duration of use. However, several reports indicate a desogestrel-driven increased risk in cervical intra-epithelial neoplasia but the results are still not conclusive. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Apri 28 Day, Azurette 28 Day, Bekyree 28 Day, Caziant 28 Day, Cesia 28 Day, Cyred 28 Day, Emoquette, Enskyce 28 Day, Freya, Isibloom 28 Day, Juleber 28 Day, Kalliga, Kariva 28 Day, Linessa, Marvelon, Mircette 28 Day, Pimtrea Pack, Reclipsen, Simliya, Velivet 28 Day, Viorele 28 Day, Volnea 28 Day •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desogestrel Désogestrel Desogestrelum •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desogestrel is a synthetic progestin used in contraception, often in combination with ethinyl estradiol. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Desoximetasone interact?

•Drug A: Adalimumab •Drug B: Desoximetasone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Desoximetasone. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Like other topical corticosteroids, desoximetasone has anti-inflammatory, antipruritic, and vasoconstrictive properties. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Desoximetasone is a potent topical corticosteroid that should not be used with occlusive dressings. It is recommended that treatment should be limited to 2 consecutive weeks and therapy should be discontinued when adequate results have been achieved. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The precise mechanism of the antiinflammatory activity of topical steroids in the treatment of steroid-responsive dermatoses, in general, is uncertain. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. This is achieved first by the drug binding to the glucocorticoid receptors which then translocates into the nucleus and binds to DNA causing various activations and repressions of genes. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may also increase percutaneous absorption. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bound to plasma proteins in varying degrees. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized, primarily in the liver, and then excreted by the kidneys. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Corticosteroids are bound to plasma proteins in varying degrees, are metabolized primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.Pharmacokinetic studies in men with Desoximetasone Cream USP, 0.25% with tagged desoximetasone showed a total of 5.2% ± 2.9% excretion in urine (4.1% ± 2.3%) and feces (1.1% ± 0.6%) •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of the material was 15 ± 2 hours (for urine) and 17 ± 2 hours (for feces) between the third and fifth trial day. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Topically applied desoximetasone can be absorbed in sufficient amounts to produce systemic effects. Symptoms of overdose include thinning of skin and suppression of adrenal cortex (decreased ability to respond to stress). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Desoxi, Topicort •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Deoxymethasone Desoximetason Desoximetasona Désoximétasone Desoximetasone Desoximetasonum Desoxymethasone •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desoximetasone is a glucocorticoid used to treat inflammatory and pruritic corticosteroid-responsive dermatoses.

Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Question: Does Adalimumab and Desoximetasone interact? Information: •Drug A: Adalimumab •Drug B: Desoximetasone •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Desoximetasone. •Extended Description: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): For the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Like other topical corticosteroids, desoximetasone has anti-inflammatory, antipruritic, and vasoconstrictive properties. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Desoximetasone is a potent topical corticosteroid that should not be used with occlusive dressings. It is recommended that treatment should be limited to 2 consecutive weeks and therapy should be discontinued when adequate results have been achieved. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The precise mechanism of the antiinflammatory activity of topical steroids in the treatment of steroid-responsive dermatoses, in general, is uncertain. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. This is achieved first by the drug binding to the glucocorticoid receptors which then translocates into the nucleus and binds to DNA causing various activations and repressions of genes. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): Topical corticosteroids can be absorbed from intact healthy skin. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusion, inflammation and/or other disease processes in the skin may also increase percutaneous absorption. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Bound to plasma proteins in varying degrees. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized, primarily in the liver, and then excreted by the kidneys. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Corticosteroids are bound to plasma proteins in varying degrees, are metabolized primarily in the liver and excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.Pharmacokinetic studies in men with Desoximetasone Cream USP, 0.25% with tagged desoximetasone showed a total of 5.2% ± 2.9% excretion in urine (4.1% ± 2.3%) and feces (1.1% ± 0.6%) •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The half-life of the material was 15 ± 2 hours (for urine) and 17 ± 2 hours (for feces) between the third and fifth trial day. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): No clearance available •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Topically applied desoximetasone can be absorbed in sufficient amounts to produce systemic effects. Symptoms of overdose include thinning of skin and suppression of adrenal cortex (decreased ability to respond to stress). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Desoxi, Topicort •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Deoxymethasone Desoximetason Desoximetasona Désoximétasone Desoximetasone Desoximetasonum Desoxymethasone •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desoximetasone is a glucocorticoid used to treat inflammatory and pruritic corticosteroid-responsive dermatoses. Output: Immunosuppressive agents may exert an additive effect on other immunosuppressive agents, leading to a greater risk of infection due to bone marrow suppression. The severity of the interaction is major.

Does Adalimumab and Desvenlafaxine interact?

•Drug A: Adalimumab •Drug B: Desvenlafaxine •Severity: MODERATE •Description: The metabolism of Desvenlafaxine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Desvenlafaxine is indicated for the treatment of major depressive disorder in adults. It has also been used off-label to treat hot flashes in menopausal women. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Desvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor. It lacks significant activity on muscarinic-cholinergic, H 1 -histaminergic, or α 1 -adrenergic receptors in vitro, or inhibitory activity against monoamine oxidase. Desvenlafaxine does not appear to exert activity against calcium, chloride, potassium and sodium ion channels and also lacks monoamine oxidase (MAO) inhibitory activity. It was also shown to lack significant activity against the cardiac potassium channel, hERG, in vitro. Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of the antidepressant action of desvenlafaxine is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Particularly, desvenlafaxine has been found to inhibit the serotonin, norepinephrine, and dopamine transporters with varying degrees of affinity. Desvenlafaxine inhibits serotonin transporters with 10 times the affinity of norepinephrine transporters, and dopamine transporters with the lowest affinity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. The time to reach maximal concentration (T max ) is estimated to be 7.5 hours after oral administration. The AUC in a 24 h dosing interval at steady state with a 100 mg dose was also calculated to be 6747 ng*h/mL, and the C max 376 ng/mL. Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine C max about 16% and had no effect on AUC. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The steady-state volume of distribution of desvenlafaxine is 3.4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of desvenlafaxine is 30% and is independent of drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. O-glucuronide conjugation is likely be catalyzed by UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17. CYP3A4 and potentially CYP2C19 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine to N,O-didesmethyl venlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Desvenlafaxine is mainly excreted in the urine. Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethyl venlafaxine) in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean terminal half-life is 11.1 hours and may be prolonged in patients with renal and/or moderate to severe hepatic impairment. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Following the administration of 100 mg of desvenlafaxine in healthy subjects from 18 to 45 years of age, the renal clearance was calculated to be 222 ± 82 mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage. Methodological limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies cannot establish or exclude any drug-associated risk during pregnancy. Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted (adj) RR 1.57, 95% CI 1.29 to 1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg/day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10 to 20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg/day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders. Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24, 95% CI 1.69 to 2.97). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64 to 1.76). The results of this study may be confounded by the effects of depression. Neonates exposed to SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Antidepressants, such as desvenlafaxine, increase the risk of suicidal thoughts and behaviors in pediatric patient. Of the 4,158 patients in pre-marketing clinical studies with desvenlafaxine, 6% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with desvenlafaxine. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose. SSRIs and SNRIs, including desvenlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert. In post-marketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine) has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. No specific antidotes for desvenlafaxine are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations. Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study. Mice received desvenlafaxine succinate at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The AUC exposure at 300 mg/kg/day dose is estimated at 10 times the AUC exposure at an adult human dose of 100 mg per day. Rats received desvenlafaxine succinate at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The AUC exposure at the highest dose is estimated at 11 (males) or 26 (females) times the AUC exposure at an adult human dose of 100 mg per day. Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay. When desvenlafaxine succinate was administered orally to male and female rats, fertility was reduced at the high dose of 300 mg/kg/day, which is 10 (males) and 19 (females) times the AUC exposure at an adult human dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day, which is 3 (males) or 5 (females) times the AUC exposure at an adult human dose of 100 mg per day. These studies did not address reversibility of the effect on fertility. The relevance of these findings to humans is not known. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Pristiq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desvenlafaxina Desvenlafaxine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desvenlafaxine is an antidepressant agent and SNRI used for the treatment of major depressive disorders in adults.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Desvenlafaxine interact? Information: •Drug A: Adalimumab •Drug B: Desvenlafaxine •Severity: MODERATE •Description: The metabolism of Desvenlafaxine can be increased when combined with Adalimumab. •Extended Description: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. •Indication (Drug A): Adalimumab is indicated for the following conditions: Moderately to severely active Rheumatoid Arthritis (RA) in adults, as monotherapy or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Moderately to severely active polyarticular Juvenile Idiopathic Arthritis (JIA) in patients two years of age and older, as monotherapy or in combination with methotrexate. Psoriatic Arthritis (PsA) in adults. Ankylosing Spondylitis (AS) in adults. Moderately to severely active Crohn’s Disease (CD) in adults and pediatric patients six years of age and older. Moderately to severely active Ulcerative Colitis (UC) in adults. Effectiveness has not been established in patients who have lost response to or were intolerant to TNF blockers. Moderate to severe chronic plaque psoriasis in adult candidates for systemic therapy or phototherapy and when other systemic therapies are medically less appropriate. Moderate to severe Hidradenitis Suppurativa (HS) in adults. Non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients two years of age and older. Adalimumab has also been used off-label to treat Pyoderma gangrenosum. •Indication (Drug B): Desvenlafaxine is indicated for the treatment of major depressive disorder in adults. It has also been used off-label to treat hot flashes in menopausal women. •Pharmacodynamics (Drug A): After treatment with adalimumab, a decrease in levels of acute phase reactant proteins of inflammation (C­ reactive protein [CRP] and erythrocyte sedimentation rate [ESR]) and serum cytokines (IL-6) was measured compared to baseline in patients diagnosed with rheumatoid arthritis. A decrease in CRP levels was also observed in patients diagnosed with Crohn’s disease. Serum levels of matrix metalloproteinases (MMP-1 and MMP-3) that lead to the tissue remodeling responsible for cartilage destruction were also found to be decreased after administration of adalimumab. A reduction in signs and symptoms of disease, the induction of clinical response, inhibition of structural damage, and improvements in physical function in adult and pediatric patients with various inflammatory conditions have been demonstrated. •Pharmacodynamics (Drug B): Desvenlafaxine is a selective serotonin and norepinephrine reuptake inhibitor. It lacks significant activity on muscarinic-cholinergic, H 1 -histaminergic, or α 1 -adrenergic receptors in vitro, or inhibitory activity against monoamine oxidase. Desvenlafaxine does not appear to exert activity against calcium, chloride, potassium and sodium ion channels and also lacks monoamine oxidase (MAO) inhibitory activity. It was also shown to lack significant activity against the cardiac potassium channel, hERG, in vitro. Electrocardiograms were obtained from 1,492 desvenlafaxine treated patients with major depressive disorder and 984 placebo-treated patients in clinical studies lasting up to 8 weeks. No clinically relevant differences were observed between desvenlafaxine treated and placebo-treated patients for QT, QTc, PR, and QRS intervals. In a thorough QTc study with prospectively determined criteria, desvenlafaxine did not cause QT prolongation. No difference was observed between placebo and desvenlafaxine treatments for the QRS interval. •Mechanism of action (Drug A): Adalimumab binds with specificity to tumor necrosis factor-alpha (TNF-alpha) and inhibits its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface tumor necrosis factor expressing cells in vitro when in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (Tumor necrosis factor-beta). TNF is a naturally occurring cytokine that plays a role in normal inflammatory and immune responses. Increased levels of TNF are found in the joint synovial fluid of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis patients, and play an imperative role in pathologic inflammation and joint destruction that are major complications of these diseases. Increased levels of TNF are also measured in psoriasis plaques. In plaque psoriasis, treatment with adalimumab may decrease the epidermal thickness and inflammatory cell infiltration. The relationship between these pharmacodynamics and the mechanism(s) by which adalimumab achieves its clinical effects is not known. Additionally, adalimumab alters biological responses that are induced/regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration during inflammation (ELAM-1, VCAM-1, and ICAM-1 with an IC50 of 1-2 X 10-10M). •Mechanism of action (Drug B): The exact mechanism of the antidepressant action of desvenlafaxine is unknown but is thought to be related to the potentiation of serotonin and norepinephrine in the central nervous system, through inhibition of their reuptake. Particularly, desvenlafaxine has been found to inhibit the serotonin, norepinephrine, and dopamine transporters with varying degrees of affinity. Desvenlafaxine inhibits serotonin transporters with 10 times the affinity of norepinephrine transporters, and dopamine transporters with the lowest affinity. •Absorption (Drug A): The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 μg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of adalimumab to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three clinical studies after a single 40 mg subcutaneous dose of adalimumab was 64%. The pharmacokinetics of adalimumab showed a linear pattern over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose. •Absorption (Drug B): The absolute oral bioavailability of desvenlafaxine after oral administration is about 80%. The time to reach maximal concentration (T max ) is estimated to be 7.5 hours after oral administration. The AUC in a 24 h dosing interval at steady state with a 100 mg dose was also calculated to be 6747 ng*h/mL, and the C max 376 ng/mL. Ingestion of a high-fat meal (800 to 1000 calories) increased desvenlafaxine C max about 16% and had no effect on AUC. •Volume of distribution (Drug A): The distribution volume (Vss) ranged from 4.7 to 6.0 L following intravenous administration of doses ranging from 0.25 to 10 mg/kg in RA patients. •Volume of distribution (Drug B): The steady-state volume of distribution of desvenlafaxine is 3.4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of desvenlafaxine is 30% and is independent of drug concentration. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Desvenlafaxine is primarily metabolized by conjugation (mediated by UGT isoforms) and, to a minor extent, through oxidative metabolism. O-glucuronide conjugation is likely be catalyzed by UGT1A1, UGT1A3, UGT2B4, UGT2B15, and UGT2B17. CYP3A4 and potentially CYP2C19 mediates the oxidative metabolism (N-demethylation) of desvenlafaxine to N,O-didesmethyl venlafaxine. The CYP2D6 metabolic pathway is not involved. The pharmacokinetics of desvenlafaxine was similar in subjects with CYP2D6 poor and extensive metabolizer phenotype. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Desvenlafaxine is mainly excreted in the urine. Approximately 45% of desvenlafaxine is excreted unchanged in urine at 72 hours after oral administration. Approximately 19% of the administered dose is excreted as the glucuronide metabolite and <5% as the oxidative metabolite (N,O-didesmethyl venlafaxine) in urine. •Half-life (Drug A): The mean terminal half-life was approximately 2 weeks, ranging from 10 to 20 days across studies. •Half-life (Drug B): The mean terminal half-life is 11.1 hours and may be prolonged in patients with renal and/or moderate to severe hepatic impairment. •Clearance (Drug A): The single-dose pharmacokinetics of adalimumab in RA patients were determined in several studies with intravenous doses ranging from 0.25 to 10 mg/kg. The systemic clearance of adalimumab is approximately 12 mL/hr. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time in RA patients. •Clearance (Drug B): Following the administration of 100 mg of desvenlafaxine in healthy subjects from 18 to 45 years of age, the renal clearance was calculated to be 222 ± 82 mL/min. •Toxicity (Drug A): Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. •Toxicity (Drug B): Published epidemiological studies of pregnant women exposed to the parent compound venlafaxine have not reported a clear association with major birth defects or miscarriage. Methodological limitations of these observational studies include possible exposure and outcome misclassification, lack of adequate controls, adjustment for confounders, and confirmatory studies; therefore, these studies cannot establish or exclude any drug-associated risk during pregnancy. Retrospective cohort studies based on claims data have shown an association between venlafaxine use and preeclampsia, compared to depressed women who did not take an antidepressant during pregnancy. One study that assessed venlafaxine exposure in the second trimester or first half of the third trimester and preeclampsia showed an increased risk compared to unexposed depressed women (adjusted (adj) RR 1.57, 95% CI 1.29 to 1.91). Preeclampsia was observed at venlafaxine doses equal to or greater than 75 mg/day and a duration of treatment >30 days. Another study that assessed venlafaxine exposure in gestational weeks 10 to 20 and preeclampsia showed an increased risk at doses equal to or greater than 150 mg/day. Available data are limited by possible outcome misclassification and possible confounding due to depression severity and other confounders. Retrospective cohort studies based on claims data have suggested an association between venlafaxine use near the time of delivery or through delivery and postpartum hemorrhage. One study showed an increased risk for postpartum hemorrhage when venlafaxine exposure occurred through delivery, compared to unexposed depressed women (adj RR 2.24, 95% CI 1.69 to 2.97). There was no increased risk in women who were exposed to venlafaxine earlier in pregnancy. Limitations of this study include possible confounding due to depression severity and other confounders. Another study showed an increased risk for postpartum hemorrhage when SNRI exposure occurred for at least 15 days in the last month of pregnancy or through delivery, compared to unexposed women (adj RR 1.64 to 1.76). The results of this study may be confounded by the effects of depression. Neonates exposed to SNRIs or SSRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Antidepressants, such as desvenlafaxine, increase the risk of suicidal thoughts and behaviors in pediatric patient. Of the 4,158 patients in pre-marketing clinical studies with desvenlafaxine, 6% were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients; however, in the short-term placebo-controlled studies, there was a higher incidence of systolic orthostatic hypotension in patients ≥65 years of age compared to patients <65 years of age treated with desvenlafaxine. For elderly patients, possible reduced renal clearance of desvenlafaxine should be considered when determining dose. SSRIs and SNRIs, including desvenlafaxine, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event. There is limited clinical trial experience with desvenlafaxine succinate overdosage in humans. However, desvenlafaxine is the major active metabolite of venlafaxine. Overdose experience reported with venlafaxine (the parent drug of desvenlafaxine) is presented below; the identical information can be found in the Overdosage section of the venlafaxine package insert. In post-marketing experience, overdose with venlafaxine (the parent drug of desvenlafaxine) has occurred predominantly in combination with alcohol and/or other drugs. The most commonly reported events in overdosage include tachycardia, changes in level of consciousness (ranging from somnolence to coma), mydriasis, seizures, and vomiting. Electrocardiogram changes (e.g., prolongation of QT interval, bundle branch block, QRS prolongation), sinus and ventricular tachycardia, bradycardia, hypotension, rhabdomyolysis, vertigo, liver necrosis, serotonin syndrome, and death have been reported. Published retrospective studies report that venlafaxine overdosage may be associated with an increased risk of fatal outcomes compared to that observed with SSRI antidepressant products, but lower than that for tricyclic antidepressants. Epidemiological studies have shown that venlafaxine-treated patients have a higher pre-existing burden of suicide risk factors than SSRI-treated patients. The extent to which the finding of an increased risk of fatal outcomes can be attributed to the toxicity of venlafaxine in overdosage, as opposed to some characteristic(s) of venlafaxine-treated patients, is not clear. No specific antidotes for desvenlafaxine are known. In managing over dosage, consider the possibility of multiple drug involvement. In case of overdose, call Poison Control Center at 1-800-222-1222 for latest recommendations. Desvenlafaxine succinate administered by oral gavage to mice and rats for 2 years did not increase the incidence of tumors in either study. Mice received desvenlafaxine succinate at dosages up to 500/300 mg/kg/day (dosage lowered after 45 weeks of dosing). The AUC exposure at 300 mg/kg/day dose is estimated at 10 times the AUC exposure at an adult human dose of 100 mg per day. Rats received desvenlafaxine succinate at dosages up to 300 mg/kg/day (males) or 500 mg/kg/day (females). The AUC exposure at the highest dose is estimated at 11 (males) or 26 (females) times the AUC exposure at an adult human dose of 100 mg per day. Desvenlafaxine was not mutagenic in the in vitro bacterial mutation assay (Ames test) and was not clastogenic in an in vitro chromosome aberration assay in cultured CHO cells, an in vivo mouse micronucleus assay, or an in vivo chromosome aberration assay in rats. Additionally, desvenlafaxine was not genotoxic in the in vitro CHO mammalian cell forward mutation assay and was negative in the in vitro BALB/c-3T3 mouse embryo cell transformation assay. When desvenlafaxine succinate was administered orally to male and female rats, fertility was reduced at the high dose of 300 mg/kg/day, which is 10 (males) and 19 (females) times the AUC exposure at an adult human dose of 100 mg per day. There was no effect on fertility at 100 mg/kg/day, which is 3 (males) or 5 (females) times the AUC exposure at an adult human dose of 100 mg per day. These studies did not address reversibility of the effect on fertility. The relevance of these findings to humans is not known. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Pristiq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Desvenlafaxina Desvenlafaxine •Summary (Drug A): Adalimumab is a monoclonal anti-tumor necrosis factor alpha antibody used in the treatment of a wide variety of inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and ankylosing spondylitis. •Summary (Drug B): Desvenlafaxine is an antidepressant agent and SNRI used for the treatment of major depressive disorders in adults. Output: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. Agents that reduce cytokine levels can normalize CYP450 formation and increase the metabolism of drugs. This interaction may significantly alter the therapeutic efficacy of CYP2C19 substrates. The severity of the interaction is moderate.