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Does Adalimumab and Sotrovimab interact?

•Drug A: Adalimumab •Drug B: Sotrovimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Sotrovimab. •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): In Europe, sotrovimab is indicated for the treatment of COVID-19 in patients ≥12 years old and weighing ≥40kg who do not require supplemental oxygen and are at high risk of progressing to severe 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): Sotrovimab is a monoclonal antibody that treats mild-to-moderate COVID-19 by binding to and neutralizing the spike protein of SARS-CoV-2. •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): Sotrovimab is a recombinant human IgG1κ monoclonal antibody that acts by binding to a conserved epitope located on the spike protein receptor-binding domain of SARS-CoV-2, the virus causing COVID-19. The epitope is highly conserved, discouraging the development of viral resistance to the antibody. This prevents the spike protein mediated binding of SARS-CoV-2 and entry into human cells. Sotrovimab does not compete with human ACE2 receptor binding and inhibits an undefined step that occurs after viral attachment and before the fusion of the viral and cell membranes. The Fc component of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that result in a longer half-life. •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 non-compartmental analysis determined that the mean Cmax after a 1 hour IV infusion of sotrovimab was 137 µg/mL and the mean Day 29 concentration was 34 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): Sotrovimab is an Fc-enhanced human immunoglobulin G (IgG), and therefore has the potential for placental transfer. •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): This antibody has undergone modifications for a potentially extended half-life and enhanced lung bioavailability. The half-life of sotrovimab is longer than Fc-unmodified IgG due to the LS modification, however, specific values are not available in the literature. •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 are currently no data available regarding an overdose with sotrovimab, and LD50 information is not available. If an overdose occurs, provide symptomatic and supportive treatment as required. •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): Sotrovimab is a monoclonal antibody for the treatment of mild-to-moderate COVID-19 in patients at increased risk for death or hospitalization.

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 Sotrovimab interact? Information: •Drug A: Adalimumab •Drug B: Sotrovimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Sotrovimab. •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): In Europe, sotrovimab is indicated for the treatment of COVID-19 in patients ≥12 years old and weighing ≥40kg who do not require supplemental oxygen and are at high risk of progressing to severe 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): Sotrovimab is a monoclonal antibody that treats mild-to-moderate COVID-19 by binding to and neutralizing the spike protein of SARS-CoV-2. •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): Sotrovimab is a recombinant human IgG1κ monoclonal antibody that acts by binding to a conserved epitope located on the spike protein receptor-binding domain of SARS-CoV-2, the virus causing COVID-19. The epitope is highly conserved, discouraging the development of viral resistance to the antibody. This prevents the spike protein mediated binding of SARS-CoV-2 and entry into human cells. Sotrovimab does not compete with human ACE2 receptor binding and inhibits an undefined step that occurs after viral attachment and before the fusion of the viral and cell membranes. The Fc component of sotrovimab includes M428L and N434S amino acid substitutions (LS modification) that result in a longer half-life. •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 non-compartmental analysis determined that the mean Cmax after a 1 hour IV infusion of sotrovimab was 137 µg/mL and the mean Day 29 concentration was 34 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): Sotrovimab is an Fc-enhanced human immunoglobulin G (IgG), and therefore has the potential for placental transfer. •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): This antibody has undergone modifications for a potentially extended half-life and enhanced lung bioavailability. The half-life of sotrovimab is longer than Fc-unmodified IgG due to the LS modification, however, specific values are not available in the literature. •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 are currently no data available regarding an overdose with sotrovimab, and LD50 information is not available. If an overdose occurs, provide symptomatic and supportive treatment as required. •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): Sotrovimab is a monoclonal antibody for the treatment of mild-to-moderate COVID-19 in patients at increased risk for death or hospitalization. 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 Spesolimab interact?

•Drug A: Adalimumab •Drug B: Spesolimab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Spesolimab. •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): Spesolimab is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. •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): Spesolimab works to reduce inflammation in GPP in a rapid and sustained manner by blocking inflammatory pathways. In clinical trials, spesolimab reduced pustules and improved other disease measures in patients with GPP, irrespective of IL36RN gene mutation status. •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): Pustular psoriasis is a type of psoriasis, a chronic and recurrent immune-mediated multisystem disorder. Based on the characteristics and distribution of pustules, the disorder has different phenotypes, such as GPP. While the pathophysiology of psoriasis is not fully understood, some pro-inflammatory cytokines involved in innate and adaptive immune systems have been implicated as key mediators of psoriatic disease. Interleukin (IL)-36 is one of those cytokines whereby unregulated activation and expression of IL-36 - often due to IL36RN gene mutations - can result in pathological autoinflammatory responses in pustular psoriasis. IL-36 is expressed in epithelial and immune cells and has three members, IL-36α, IL-36β, and IL-36γ, that bind to a receptor complex to activate pro-inflammatory and pro-fibrotic downstream signalling pathways, such as increased expression and actions of pro-inflammatory cells and factors. The heterodimeric receptor complex IL-36R comprises an IL-1RL2 subunit - to which IL-36 binds - and an IL-1RAcP co-receptor. The exact mechanism of action of spesolimab in managing psoriatic flares is unclear; however, it is believed to ameliorate inflammation by inhibiting IL-36 signalling. Spesolimab binds to the IL-36R receptor complex, preventing the binding of IL-36 downstream activation of receptor signalling 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): A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP, and patients with other diseases. After a single intravenous dose of 900 mg of spesolimab, the population PK model-estimated AUC 0-∞ (95% CI) and C max (95% CI) in a typical anti-drug antibody (ADA)-negative patient with GPP were 4750 (4510, 4970) mcg x day/mL and 238 (218, 256) mcg/mL, 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): Based on the population pharmacokinetic analysis, the typical total volume of distribution at steady state was 6.4 L. •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): The metabolic pathway of spesolimab-sbzo has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab-sbzo is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): There is no 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): The terminal half-life is 25.5 (24.4, 26.3) 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): In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab-sbzo clearance (95% CI) in a typical GPP patient without anti-drug antibodies, weighing 70 kg was 0.184 (0.175, 0.194) 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): There is no information available regarding the LD 50, acute toxicity profile, and overdose of spesolimab. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Spevigo •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): Spesolimab is an interleukin-36 receptor antagonist used to treat generalized pustular psoriasis flares in adults.

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 Spesolimab interact? Information: •Drug A: Adalimumab •Drug B: Spesolimab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Spesolimab. •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): Spesolimab is indicated for the treatment of generalized pustular psoriasis (GPP) in adults and pediatric patients 12 years of age and older and weighing at least 40 kg. •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): Spesolimab works to reduce inflammation in GPP in a rapid and sustained manner by blocking inflammatory pathways. In clinical trials, spesolimab reduced pustules and improved other disease measures in patients with GPP, irrespective of IL36RN gene mutation status. •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): Pustular psoriasis is a type of psoriasis, a chronic and recurrent immune-mediated multisystem disorder. Based on the characteristics and distribution of pustules, the disorder has different phenotypes, such as GPP. While the pathophysiology of psoriasis is not fully understood, some pro-inflammatory cytokines involved in innate and adaptive immune systems have been implicated as key mediators of psoriatic disease. Interleukin (IL)-36 is one of those cytokines whereby unregulated activation and expression of IL-36 - often due to IL36RN gene mutations - can result in pathological autoinflammatory responses in pustular psoriasis. IL-36 is expressed in epithelial and immune cells and has three members, IL-36α, IL-36β, and IL-36γ, that bind to a receptor complex to activate pro-inflammatory and pro-fibrotic downstream signalling pathways, such as increased expression and actions of pro-inflammatory cells and factors. The heterodimeric receptor complex IL-36R comprises an IL-1RL2 subunit - to which IL-36 binds - and an IL-1RAcP co-receptor. The exact mechanism of action of spesolimab in managing psoriatic flares is unclear; however, it is believed to ameliorate inflammation by inhibiting IL-36 signalling. Spesolimab binds to the IL-36R receptor complex, preventing the binding of IL-36 downstream activation of receptor signalling 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): A population pharmacokinetic model was developed based on data collected from healthy subjects, patients with GPP, and patients with other diseases. After a single intravenous dose of 900 mg of spesolimab, the population PK model-estimated AUC 0-∞ (95% CI) and C max (95% CI) in a typical anti-drug antibody (ADA)-negative patient with GPP were 4750 (4510, 4970) mcg x day/mL and 238 (218, 256) mcg/mL, 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): Based on the population pharmacokinetic analysis, the typical total volume of distribution at steady state was 6.4 L. •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): The metabolic pathway of spesolimab-sbzo has not been characterized. As a humanized IgG1 monoclonal antibody, spesolimab-sbzo is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): There is no 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): The terminal half-life is 25.5 (24.4, 26.3) 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): In the linear dose range (0.3 to 20 mg/kg), based on the population PK model, spesolimab-sbzo clearance (95% CI) in a typical GPP patient without anti-drug antibodies, weighing 70 kg was 0.184 (0.175, 0.194) 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): There is no information available regarding the LD 50, acute toxicity profile, and overdose of spesolimab. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Spevigo •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): Spesolimab is an interleukin-36 receptor antagonist used to treat generalized pustular psoriasis flares in adults. 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 St. John's Wort interact?

•Drug A: Adalimumab •Drug B: St. John's Wort •Severity: MODERATE •Description: The metabolism of St. John's Wort 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. •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

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 St. John's Wort interact? Information: •Drug A: Adalimumab •Drug B: St. John's Wort •Severity: MODERATE •Description: The metabolism of St. John's Wort 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. •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: The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Stiripentol interact?

•Drug A: Adalimumab •Drug B: Stiripentol •Severity: MODERATE •Description: The metabolism of Stiripentol 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): In the US, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in patients taking clobazam who are 6 months of age and older and weighing 7 kg or more. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome. In Europe and Canada, stiripentol is indicated for use as adjunctive therapy with clobazam and valproate to refractory generalized tonic-clonic seizures in patients with Dravet syndrome in infancy whose seizures are not adequately controlled with clobazam and valproate alone. •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): Stiripentol is an antiepileptic agent that works to reduce seizure frequency. It demonstrates anticonvulsant properties when administered alone and may potentiate GABAergic inhibition via several proposed mechanisms. It provides a therapeutic advantage in improving the efficacy of other antiepileptic drugs by inhibiting cytochrome P450 enzymes that normally metabolize those drugs. The anticonvulsant activity of stiripentol is age-dependent, with increased efficacy in younger 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): The mechanism by which stiripentol exerts its anticonvulsant effect in humans has not been fully elucidated. Possible mechanisms of action include direct effects mediated through the gamma-aminobutyric acid GABA A receptor and indirect effects involving inhibition of cytochrome P450 activity with a resulting increase in blood levels of clobazam and its active metabolite. Stiripentol is a positive allosteric modulator of GABA A receptors in the brain that enhances the opening duration of the channel by binding to a site different than the benzodiazepine binding site. It binds to GABA A receptors containing any of the α, β, γ, or δ-subunits but displays the most potent potency when bound to receptors containing α3 or δ subunits. Stiripentol also binds to GABA A receptor-dependent chloride channels via a barbiturate-like mechanism. Stiripentol potentiates GABA transmission by enhancing the release of GABA, reducing synaptosomal uptake of GABA, and inhibiting GABA transaminase-mediated breakdown of GABA. Stiripentol is an inhibitor of lactate dehydrogenase (LDH), which is involved in the energy metabolism of neurons and regulation of neuronal excitation. The drug binds to the site separate from the enzyme's lactate and pyruvate binding sites, thereby inhibiting both pyruvate-to-lactate conversion and lactate-to-pyruvate conversion. By inhibiting LDH, stiripentol may induce hyperpolarization, thereby reducing neuronal excitability. LDH inhibitors, including stiripentol, mimic a ketogenic diet, where the energy source in the brain is switched from glucose to mainly ketone bodies. The ketone bodies directly regulate neuronal excitation and seizures via ATP-sensitive potassium channels and vesicular glutamate transporters. Stiripentol is also suggested to exhibit neuroprotective properties, which may reduce injury caused by oxygen-glucose deprivation and glutamate excess. •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, stiripentol is quickly and readily absorbed with a median T max of two to three hours. The systemic exposure increases dose-proportionally. Stiripentol has a low bioavailability due to water insolubility and extensive metabolism. •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 average volume of distribution is 1.03 L/kg but does not display a dose-dependent relationship. Following administration, stiripentol enters the brain and accumulates in the cerebellum and medulla. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of stiripentol is 99%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Stiripentol is extensively metabolized. About 13 different metabolites have been found in urine. The main metabolic processes are demethylenation (oxidative cleavage of the methylenedioxy ring system) and glucuronidation, although precise identification of the enzymes involved has not yet been achieved. Other metabolic pathways include O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure. In vitro studies suggested that the phase I metabolism of stiripentol is catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Stiripentol is mainly eliminated via metabolism. Its metabolites are excreted mainly via the kidney. Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose whereas a further 13-24% was recovered in feces 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): The elimination half life is approximately ranges from 4.5 to 13 hours, in a dose-dependent manner. •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): Plasma clearance decreases markedly at high doses; it falls from approximately 40 L/kg/day at the dose of 600 mg/day to about 8 L/kg/day at the dose of 2,400 mg. Clearance is decreased after repeated administration of stiripentol, probably due to inhibition of the cytochrome P450 isoenzymes responsible for its metabolism. •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 >3 g/kg. There is limited clinical data on stiripentol overdose in humans. In mice, high doses of stiripentol (600 to 1800 mg/kg i.p.) caused decreased motor activity and respiration. Overdose should be managed with supportive and symptomatic treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Diacomit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estiripentol Stiripentol Stiripentolum •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): Stiripentol is an antiepileptic agent used in combination with other anticonvulsants to treat seizures associated with Dravet 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 CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Stiripentol interact? Information: •Drug A: Adalimumab •Drug B: Stiripentol •Severity: MODERATE •Description: The metabolism of Stiripentol 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): In the US, stiripentol is indicated for the treatment of seizures associated with Dravet syndrome in patients taking clobazam who are 6 months of age and older and weighing 7 kg or more. There are no clinical data to support the use of stiripentol as monotherapy in Dravet syndrome. In Europe and Canada, stiripentol is indicated for use as adjunctive therapy with clobazam and valproate to refractory generalized tonic-clonic seizures in patients with Dravet syndrome in infancy whose seizures are not adequately controlled with clobazam and valproate alone. •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): Stiripentol is an antiepileptic agent that works to reduce seizure frequency. It demonstrates anticonvulsant properties when administered alone and may potentiate GABAergic inhibition via several proposed mechanisms. It provides a therapeutic advantage in improving the efficacy of other antiepileptic drugs by inhibiting cytochrome P450 enzymes that normally metabolize those drugs. The anticonvulsant activity of stiripentol is age-dependent, with increased efficacy in younger 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): The mechanism by which stiripentol exerts its anticonvulsant effect in humans has not been fully elucidated. Possible mechanisms of action include direct effects mediated through the gamma-aminobutyric acid GABA A receptor and indirect effects involving inhibition of cytochrome P450 activity with a resulting increase in blood levels of clobazam and its active metabolite. Stiripentol is a positive allosteric modulator of GABA A receptors in the brain that enhances the opening duration of the channel by binding to a site different than the benzodiazepine binding site. It binds to GABA A receptors containing any of the α, β, γ, or δ-subunits but displays the most potent potency when bound to receptors containing α3 or δ subunits. Stiripentol also binds to GABA A receptor-dependent chloride channels via a barbiturate-like mechanism. Stiripentol potentiates GABA transmission by enhancing the release of GABA, reducing synaptosomal uptake of GABA, and inhibiting GABA transaminase-mediated breakdown of GABA. Stiripentol is an inhibitor of lactate dehydrogenase (LDH), which is involved in the energy metabolism of neurons and regulation of neuronal excitation. The drug binds to the site separate from the enzyme's lactate and pyruvate binding sites, thereby inhibiting both pyruvate-to-lactate conversion and lactate-to-pyruvate conversion. By inhibiting LDH, stiripentol may induce hyperpolarization, thereby reducing neuronal excitability. LDH inhibitors, including stiripentol, mimic a ketogenic diet, where the energy source in the brain is switched from glucose to mainly ketone bodies. The ketone bodies directly regulate neuronal excitation and seizures via ATP-sensitive potassium channels and vesicular glutamate transporters. Stiripentol is also suggested to exhibit neuroprotective properties, which may reduce injury caused by oxygen-glucose deprivation and glutamate excess. •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, stiripentol is quickly and readily absorbed with a median T max of two to three hours. The systemic exposure increases dose-proportionally. Stiripentol has a low bioavailability due to water insolubility and extensive metabolism. •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 average volume of distribution is 1.03 L/kg but does not display a dose-dependent relationship. Following administration, stiripentol enters the brain and accumulates in the cerebellum and medulla. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of stiripentol is 99%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Stiripentol is extensively metabolized. About 13 different metabolites have been found in urine. The main metabolic processes are demethylenation (oxidative cleavage of the methylenedioxy ring system) and glucuronidation, although precise identification of the enzymes involved has not yet been achieved. Other metabolic pathways include O-methylation of catechol metabolites, hydroxylation of the t-butyl group, and conversion of the allylic alcohol side-chain to the isomeric 3-pentanone structure. In vitro studies suggested that the phase I metabolism of stiripentol is catalyzed by CYP1A2, CYP2C19 and CYP3A4 and possibly other enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Stiripentol is mainly eliminated via metabolism. Its metabolites are excreted mainly via the kidney. Urinary metabolites of stiripentol accounted collectively for the majority (73%) of an oral acute dose whereas a further 13-24% was recovered in feces 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): The elimination half life is approximately ranges from 4.5 to 13 hours, in a dose-dependent manner. •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): Plasma clearance decreases markedly at high doses; it falls from approximately 40 L/kg/day at the dose of 600 mg/day to about 8 L/kg/day at the dose of 2,400 mg. Clearance is decreased after repeated administration of stiripentol, probably due to inhibition of the cytochrome P450 isoenzymes responsible for its metabolism. •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 >3 g/kg. There is limited clinical data on stiripentol overdose in humans. In mice, high doses of stiripentol (600 to 1800 mg/kg i.p.) caused decreased motor activity and respiration. Overdose should be managed with supportive and symptomatic treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Diacomit •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estiripentol Stiripentol Stiripentolum •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): Stiripentol is an antiepileptic agent used in combination with other anticonvulsants to treat seizures associated with Dravet 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 CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Streptozocin interact?

•Drug A: Adalimumab •Drug B: Streptozocin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Streptozocin. •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 malignant neoplasms of pancreas (metastatic islet cell 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): Streptozocin is an antitumour antibiotic consisting of a nitrosourea moiety interposed between a methyl group and a glucosamine. Streptozocin is indicated in the treatment of metastatic islet cell carcinoma of the pancreas. Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal 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): Although its mechanism of action is not completely clear, streptozocin is known to inhibit DNA synthesis, interfere with biochemical reactions of NAD and NADH, and inhibit some enzymes involved in gluconeogenesis. Its activity appears to occur as a result of formation of methylcarbonium ions, which alkylate or bind with many intracellular molecular structures including nucleic acids. Its cytotoxic action is probably due to cross-linking of strands of DNA, resulting in inhibition of DNA 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): Poor oral absorption (17-25%) •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): Primarily hepatic •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. •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): 5-15 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): Symptoms of overdose include nausea and vomiting, anorexia, myelosuppression; and nephrotoxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zanosar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estreptozocina Streptozocin Streptozocine Streptozocinium Streptozocinum Streptozotocin •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): Streptozocin is a nitrosourea antineoplastic agent used in the treatment of metastatic pancreatic islet cell carcinoma.

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 Streptozocin interact? Information: •Drug A: Adalimumab •Drug B: Streptozocin •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Streptozocin. •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 malignant neoplasms of pancreas (metastatic islet cell 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): Streptozocin is an antitumour antibiotic consisting of a nitrosourea moiety interposed between a methyl group and a glucosamine. Streptozocin is indicated in the treatment of metastatic islet cell carcinoma of the pancreas. Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal 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): Although its mechanism of action is not completely clear, streptozocin is known to inhibit DNA synthesis, interfere with biochemical reactions of NAD and NADH, and inhibit some enzymes involved in gluconeogenesis. Its activity appears to occur as a result of formation of methylcarbonium ions, which alkylate or bind with many intracellular molecular structures including nucleic acids. Its cytotoxic action is probably due to cross-linking of strands of DNA, resulting in inhibition of DNA 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): Poor oral absorption (17-25%) •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): Primarily hepatic •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. •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): 5-15 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): Symptoms of overdose include nausea and vomiting, anorexia, myelosuppression; and nephrotoxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zanosar •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Estreptozocina Streptozocin Streptozocine Streptozocinium Streptozocinum Streptozotocin •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): Streptozocin is a nitrosourea antineoplastic agent used in the treatment of metastatic pancreatic islet cell carcinoma. 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 Sulfadiazine interact?

•Drug A: Adalimumab •Drug B: Sulfadiazine •Severity: MODERATE •Description: The metabolism of Sulfadiazine 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): For the treatment of rheumatic fever and meningococcal meningitis •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): Sulfadiazine is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organisms. However, many strains of an individual species may be resistant. Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of p -aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally. However, parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus. •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): Sulfadiazine is a competitive inhibitor of the bacterial enzyme dihydropteroate synthetase. This enzyme is needed for the proper processing of para-aminobenzoic acid (PABA) which is essential for folic acid synthesis. The inhibited reaction is necessary in these organisms for the synthesis of folic acid. •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): Sulfadiazine is excreted largely 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): 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 LD 50 in mouse is 1500 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): 2-sulfanilamidopyrimidine Sulfadiazin Sulfadiazina Sulfadiazine Sulfadiazinum Sulfapyrimidine Sulphadiazine •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): Sulfadiazine is a sulfonamide antibiotic used in a variety of infections, such as urinary tract infections, trachoma, and chancroid.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Sulfadiazine interact? Information: •Drug A: Adalimumab •Drug B: Sulfadiazine •Severity: MODERATE •Description: The metabolism of Sulfadiazine 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): For the treatment of rheumatic fever and meningococcal meningitis •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): Sulfadiazine is a sulfonamide antibiotic. The sulfonamides are synthetic bacteriostatic antibiotics with a wide spectrum against most gram-positive and many gram-negative organisms. However, many strains of an individual species may be resistant. Sulfonamides inhibit multiplication of bacteria by acting as competitive inhibitors of p -aminobenzoic acid in the folic acid metabolism cycle. Bacterial sensitivity is the same for the various sulfonamides, and resistance to one sulfonamide indicates resistance to all. Most sulfonamides are readily absorbed orally. However, parenteral administration is difficult, since the soluble sulfonamide salts are highly alkaline and irritating to the tissues. The sulfonamides are widely distributed throughout all tissues. High levels are achieved in pleural, peritoneal, synovial, and ocular fluids. Although these drugs are no longer used to treat meningitis, CSF levels are high in meningeal infections. Their antibacterial action is inhibited by pus. •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): Sulfadiazine is a competitive inhibitor of the bacterial enzyme dihydropteroate synthetase. This enzyme is needed for the proper processing of para-aminobenzoic acid (PABA) which is essential for folic acid synthesis. The inhibited reaction is necessary in these organisms for the synthesis of folic acid. •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): Sulfadiazine is excreted largely 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): 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 LD 50 in mouse is 1500 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): 2-sulfanilamidopyrimidine Sulfadiazin Sulfadiazina Sulfadiazine Sulfadiazinum Sulfapyrimidine Sulphadiazine •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): Sulfadiazine is a sulfonamide antibiotic used in a variety of infections, such as urinary tract infections, trachoma, and chancroid. 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 Sulfasalazine interact?

•Drug A: Adalimumab •Drug B: Sulfasalazine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Sulfasalazine. •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): In the US, sulfasalazine is indicated to treat mild to moderate ulcerative colitis and to prolong the remission period between acute attacks of ulcerative colitis. Sulfasalazine is also indicated as an adjunct therapy in severe ulcerative colitis. For the delayed-release tablet formulation, sulfasalazine is also indicated to treat rheumatoid arthritis in pediatric patients who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs or polyarticular-course juvenile rheumatoid arthritis with the same patients' characteristics. •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 mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid have indicated that the major therapeutic action may reside in the 5-aminosalicylic acid moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is 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): Although the exact mechanism of action of sulfasalazine is not fully understood, it is thought to be mediated through the inhibition of various inflammatory molecules. Research have found that sulfasalazine and its metabolites, mesalazine and sulfapyridine, can inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathway. Specific enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta. •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 administration of 1 g of sulfasalazine to 9 healthy males, less than 15% of a dose of sulfasalazine is absorbed as the parent drug. Detectable serum concentrations of sulfasalazine have been found in healthy subjects within 90 minutes after ingestion. Maximum concentrations of sulfasalazine occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 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): Following intravenous injection, the calculated volume of distribution for sulfasalazine was 7.5 ± 1.6 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sulfasalazine is highly bound to albumin (>99.3%) while sulfapyridine is only about 70% bound to albumin. Acetylsulfapyridine, the principal metabolite of sulfapyridine, is approximately 90% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In the intestine, sulfasalazine is metabolized by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid. Of the two species, sulfapyridine is relatively well absorbed from the intestine and highly metabolized, while 5-aminosalicylic acid is much less well absorbed. Approximately 15% of a dose of sulfasalazine is absorbed as the parent drug and is metabolized to some extent in the liver to the same two species. Sulfapyridine can also be metabolized to 5-hydroxysulfapyridine and N-acetyl-5-hydroxy sulfapyridine. 5-aminosalicylic acid is primarily metabolized in both the liver and intestine to N-acetyl-5 aminosalicylic acid via a non-acetylation phenotype-dependent route. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid 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 observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hours. In fast acetylators, the mean plasma half-life of sulfapyridine is 10.4 hours while in slow acetylators, it is 14.8 hours. Due to low plasma levels produced by 5-aminosalicylic acid after oral administration, reliable estimates of plasma half-life are not possible. •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 calculated clearance of sulfasalazine following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total 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): Two-year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2), and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed an equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated IBD pregnancies as well as to pregnancies in the general population. A study of 1,455 pregnancies associated with exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation. A review of the medical literature covering 1,155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population. No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Azulfidine, Salazopyrin, Salazopyrin En-tabs •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azopyrin Salazosulfapiridina Salazosulfapyridine Salazosulfapyridinum Salicylazosulfapyridine Sulfasalazin Sulfasalazina Sulfasalazine Sulfasalazinum •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): Sulfasalazine is a salicylate used to treat Crohn's disease, ulcerative colitis, and rheumatoid arthritis.

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 Sulfasalazine interact? Information: •Drug A: Adalimumab •Drug B: Sulfasalazine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Sulfasalazine. •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): In the US, sulfasalazine is indicated to treat mild to moderate ulcerative colitis and to prolong the remission period between acute attacks of ulcerative colitis. Sulfasalazine is also indicated as an adjunct therapy in severe ulcerative colitis. For the delayed-release tablet formulation, sulfasalazine is also indicated to treat rheumatoid arthritis in pediatric patients who have responded inadequately to salicylates or other nonsteroidal anti-inflammatory drugs or polyarticular-course juvenile rheumatoid arthritis with the same patients' characteristics. •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 mode of action of sulfasalazine or its metabolites, 5-aminosalicylic acid and sulfapyridine, is still under investigation but may be related to the anti-inflammatory and/or immunomodulatory properties that have been observed in animal and in vitro models, to its affinity for connective tissue, and/or to the relatively high concentration it reaches in serous fluids, the liver, and intestinal walls, as demonstrated in autoradiographic studies in animals. In ulcerative colitis, clinical studies utilizing rectal administration of sulfasalazine, sulfapyridine, and 5-aminosalicylic acid have indicated that the major therapeutic action may reside in the 5-aminosalicylic acid moiety. The relative contribution of the parent drug and the major metabolites in rheumatoid arthritis is 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): Although the exact mechanism of action of sulfasalazine is not fully understood, it is thought to be mediated through the inhibition of various inflammatory molecules. Research have found that sulfasalazine and its metabolites, mesalazine and sulfapyridine, can inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathway. Specific enzymes that were investigated include phospholipase A2, cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX2), and arachidonate 5-lipoxygenase. Inhibitory activities on other non-arachidonic acid derivatives have also been observed, including PPAR gamma, NF-Kb, and IkappaB kinases alpha and beta. •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 administration of 1 g of sulfasalazine to 9 healthy males, less than 15% of a dose of sulfasalazine is absorbed as the parent drug. Detectable serum concentrations of sulfasalazine have been found in healthy subjects within 90 minutes after ingestion. Maximum concentrations of sulfasalazine occur between 3 and 12 hours post-ingestion, with the mean peak concentration (6 μg/mL) occurring at 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): Following intravenous injection, the calculated volume of distribution for sulfasalazine was 7.5 ± 1.6 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Sulfasalazine is highly bound to albumin (>99.3%) while sulfapyridine is only about 70% bound to albumin. Acetylsulfapyridine, the principal metabolite of sulfapyridine, is approximately 90% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In the intestine, sulfasalazine is metabolized by intestinal bacteria to sulfapyridine and 5-aminosalicylic acid. Of the two species, sulfapyridine is relatively well absorbed from the intestine and highly metabolized, while 5-aminosalicylic acid is much less well absorbed. Approximately 15% of a dose of sulfasalazine is absorbed as the parent drug and is metabolized to some extent in the liver to the same two species. Sulfapyridine can also be metabolized to 5-hydroxysulfapyridine and N-acetyl-5-hydroxy sulfapyridine. 5-aminosalicylic acid is primarily metabolized in both the liver and intestine to N-acetyl-5 aminosalicylic acid via a non-acetylation phenotype-dependent route. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Absorbed sulfapyridine and 5-aminosalicylic acid and their metabolites are primarily eliminated in the urine either as free metabolites or as glucuronide conjugates. The majority of 5-ASA stays within the colonic lumen and is excreted as 5-aminosalicylic acid and acetyl-5-aminosalicylic acid 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 observed plasma half-life for intravenous sulfasalazine is 7.6 ± 3.4 hours. In fast acetylators, the mean plasma half-life of sulfapyridine is 10.4 hours while in slow acetylators, it is 14.8 hours. Due to low plasma levels produced by 5-aminosalicylic acid after oral administration, reliable estimates of plasma half-life are not possible. •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 calculated clearance of sulfasalazine following intravenous administration was 1 L/hr. Renal clearance was estimated to account for 37% of total 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): Two-year oral carcinogenicity studies were conducted in male and female F344/N rats and B6C3F1 mice. Sulfasalazine was tested at 84 (496 mg/m2), 168 (991 mg/m2), and 337.5 (1991 mg/m2) mg/kg/day doses in rats. A statistically significant increase in the incidence of urinary bladder transitional cell papillomas was observed in male rats. In female rats, two (4%) of the 337.5 mg/kg rats had transitional cell papilloma of the kidney. The increased incidence of neoplasms in the urinary bladder and kidney of rats was also associated with an increase in renal calculi formation and hyperplasia of transitional cell epithelium. For the mouse study, sulfasalazine was tested at 675 (2025 mg/m2), 1350 (4050 mg/m2), and 2700 (8100 mg/m2) mg/kg/day. The incidence of hepatocellular adenoma or carcinoma in male and female mice was significantly greater than the control at all doses tested. Sulfasalazine did not show mutagenicity in the bacterial reverse mutation assay (Ames test) and in L51784 mouse lymphoma cell assay at the HGPRT gene. However, sulfasalazine showed an equivocal mutagenic response in the micronucleus assay of mouse and rat bone marrow and mouse peripheral RBC and in the sister chromatid exchange, chromosomal aberration, and micronucleus assays in lymphocytes obtained from humans. Impairment of male fertility was observed in reproductive studies performed in rats at a dose of 800 mg/kg/day (4800 mg/m2). Oligospermia and infertility have been described in men treated with sulfasalazine. Withdrawal of the drug appears to reverse these effects. There are no adequate and well-controlled studies of sulfasalazine in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 6 times the human maintenance dose of 2 g/day based on body surface area and have revealed no evidence of impaired female fertility or harm to the fetus due to sulfasalazine. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. There have been case reports of neural tube defects (NTDs) in infants born to mothers who were exposed to sulfasalazine during pregnancy, but the role of sulfasalazine in these defects has not been established. However, oral sulfasalazine inhibits the absorption and metabolism of folic acid which may interfere with folic acid supplementation (see Drug Interactions) and diminish the effect of periconceptional folic acid supplementation that has been shown to decrease the risk of NTDs. A national survey evaluated the outcome of pregnancies associated with inflammatory bowel disease (IBD). In a group of 186 women treated with sulfasalazine alone or sulfasalazine and concomitant steroid therapy, the incidence of fetal morbidity and mortality was comparable to that for 245 untreated IBD pregnancies as well as to pregnancies in the general population. A study of 1,455 pregnancies associated with exposure to sulfonamides indicated that this group of drugs, including sulfasalazine, did not appear to be associated with fetal malformation. A review of the medical literature covering 1,155 pregnancies in women with ulcerative colitis suggested that the outcome was similar to that expected in the general population. No clinical studies have been performed to evaluate the effect of sulfasalazine on the growth development and functional maturation of children whose mothers received the drug during pregnancy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Azulfidine, Salazopyrin, Salazopyrin En-tabs •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Azopyrin Salazosulfapiridina Salazosulfapyridine Salazosulfapyridinum Salicylazosulfapyridine Sulfasalazin Sulfasalazina Sulfasalazine Sulfasalazinum •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): Sulfasalazine is a salicylate used to treat Crohn's disease, ulcerative colitis, and rheumatoid arthritis. 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 Sunitinib interact?

•Drug A: Adalimumab •Drug B: Sunitinib •Severity: MAJOR •Description: The metabolism of Sunitinib 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): Sunitinib is indicated for the following conditions: Treatment of adult patients with gastrointestinal stromal tumor (GIST) following disease progression on (or intolerance to) imatinib mesylate Treatment of adult patients with advanced renal cell carcinoma (RCC) Adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic 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): Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006. •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): Sunitinib is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRb), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. •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): Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib may be taken with or without food. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC. •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): 2230 L (apparent volume of distribution, Vd/F) •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binding of sunitinib and its primary metabolite to human plasma protein in vitro was 95% and 90%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% 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): Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 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): 34 - 62 L/h [Total oral 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 maximally tolerated dose for rat, mouse, and dog when given orally is greater than 500 mg/kg. The maximally tolerated dose of a non-human primate is greater 1200 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Sutent •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): Sunitinib is a receptor tyrosine kinase inhibitor and chemotherapeutic agent used for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Sunitinib interact? Information: •Drug A: Adalimumab •Drug B: Sunitinib •Severity: MAJOR •Description: The metabolism of Sunitinib 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): Sunitinib is indicated for the following conditions: Treatment of adult patients with gastrointestinal stromal tumor (GIST) following disease progression on (or intolerance to) imatinib mesylate Treatment of adult patients with advanced renal cell carcinoma (RCC) Adjuvant treatment of adult patients at high risk of recurrent RCC following nephrectomy Treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in adult patients with unresectable locally advanced or metastatic 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): Sunitinib is an oral, small-molecule, multi-targeted receptor tyrosine kinase (RTK) inhibitor that was approved by the FDA on January 26, 2006. •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): Sunitinib is a small molecule that inhibits multiple RTKs, some of which are implicated in tumor growth, pathologic angiogenesis, and metastatic progression of cancer. Sunitinib was evaluated for its inhibitory activity against a variety of kinases (>80 kinases) and was identified as an inhibitor of platelet-derived growth factor receptors (PDGFRa and PDGFRb), vascular endothelial growth factor receptors (VEGFR1, VEGFR2 and VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony stimulating factor receptor Type 1 (CSF-1R), and the glial cell-line derived neurotrophic factor receptor (RET). Sunitinib inhibition of the activity of these RTKs has been demonstrated in biochemical and cellular assays, and inhibition of function has been demonstrated in cell proliferation assays. The primary metabolite exhibits similar potency compared to sunitinib in biochemical and cellular assays. •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): Maximum plasma concentrations (Cmax) of sunitinib are generally observed between 6 and 12 hours (Tmax) following oral administration. Food has no effect on the bioavailability of sunitinib. Sunitinib may be taken with or without food. The pharmacokinetics were similar in healthy volunteers and in the solid tumor patient populations tested, including patients with GIST and RCC. •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): 2230 L (apparent volume of distribution, Vd/F) •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binding of sunitinib and its primary metabolite to human plasma protein in vitro was 95% and 90%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Sunitinib is metabolized primarily by the cytochrome P450 enzyme, CYP3A4, to produce its primary active metabolite, which is further metabolized by CYP3A4. Elimination is primarily via feces. In a human mass balance study of [14C]sunitinib, 61% of the dose was eliminated in feces, with renal elimination accounting for 16% 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): Following administration of a single oral dose in healthy volunteers, the terminal half-lives of sunitinib and its primary active metabolite are approximately 40 to 60 hours and 80 to 110 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): 34 - 62 L/h [Total oral 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 maximally tolerated dose for rat, mouse, and dog when given orally is greater than 500 mg/kg. The maximally tolerated dose of a non-human primate is greater 1200 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Sutent •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): Sunitinib is a receptor tyrosine kinase inhibitor and chemotherapeutic agent used for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST). 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 Sutimlimab interact?

•Drug A: Adalimumab •Drug B: Sutimlimab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Sutimlimab. •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): Sutimlimab is indicated to treat hemolysis in adults with cold agglutinin disease (CAD) and decrease the need for red blood cell transfusion in these 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): Following a single sutimlimab injection, >90% inhibition of the complement pathway was observed, and this inhibition was sustained when concentrations of sutimlimab were ≥100 mcg/mL. As sutimlimab can impair the complement-mediated immune response, patients requiring therapy should receive all appropriate vaccinations against encapsulated bacteria at least 2 weeks prior to its initiation. Patients undergoing treatment with sutimlimab are at a higher risk of serious infections, especially those caused by encapsulated bacteria such as Neisseria meningitides or Streptococcus pneumoniae, and should be monitored closely throughout therapy for evidence of developing or ongoing 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): Hemolysis associated with cold agglutinin disease is driven by the activation of the complement system. Cold agglutinins transiently bind erythrocytes as they circulate through cooler parts of the body (e.g. the extremities) - as they circulate back to warmer areas, C1q esterase activates C4 and C2, which generates C3 convertase, an enzyme which cleaves C3 into C3a and C3b. At this stage, the erythrocytes tagged with C3b can be sequestered by macrophages in the reticuloendothelial system, ultimately leading to extravascular hemolysis. Alternatively, C3b may be further cleaved into C3c and C3d - if complement activation continues past the C3 step, the membrane attack complex with C5b-C9 may form, which causes intravascular hemolysis. Sutimlimab is a humanized IgG4 monoclonal antibody targeted at the complement C1s subunit, a serine protease responsible for the activation of the classic complement pathway. By inhibiting the complement cascade at the level of C1s, sutimlimab prevents the deposition of complement opsinins on erythrocytes, thus preventing their eventual hemolysis. •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 at the approved weight-based recommended dosage, the exposure to sutimlimab increases proportionately with increasing dosage. Steady-state concentrations are achieved by week 7 of therapy. •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): At steady-state, the volume of distribution of sutimlimab in patients with cold agglutinin disease was approximately 5.8 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): As with other therapeutic proteins, sutimlimab likely undergoes catabolism 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): 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): At the approved recommended dosage, the terminal elimination half-life of sutimlimab is 21 days. The half-life of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •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 the approved recommended dosage, the clearance of sutimlimab is 0.14 L/day. The clearance of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •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): Enjaymo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sutimlimab •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): Sutimlimab is a monoclonal antibody directed towards complement subunit C1s used to reduce the need for blood transfusion due to hemolysis in patients with cold agglutinin disease.

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 Sutimlimab interact? Information: •Drug A: Adalimumab •Drug B: Sutimlimab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Sutimlimab. •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): Sutimlimab is indicated to treat hemolysis in adults with cold agglutinin disease (CAD) and decrease the need for red blood cell transfusion in these 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): Following a single sutimlimab injection, >90% inhibition of the complement pathway was observed, and this inhibition was sustained when concentrations of sutimlimab were ≥100 mcg/mL. As sutimlimab can impair the complement-mediated immune response, patients requiring therapy should receive all appropriate vaccinations against encapsulated bacteria at least 2 weeks prior to its initiation. Patients undergoing treatment with sutimlimab are at a higher risk of serious infections, especially those caused by encapsulated bacteria such as Neisseria meningitides or Streptococcus pneumoniae, and should be monitored closely throughout therapy for evidence of developing or ongoing 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): Hemolysis associated with cold agglutinin disease is driven by the activation of the complement system. Cold agglutinins transiently bind erythrocytes as they circulate through cooler parts of the body (e.g. the extremities) - as they circulate back to warmer areas, C1q esterase activates C4 and C2, which generates C3 convertase, an enzyme which cleaves C3 into C3a and C3b. At this stage, the erythrocytes tagged with C3b can be sequestered by macrophages in the reticuloendothelial system, ultimately leading to extravascular hemolysis. Alternatively, C3b may be further cleaved into C3c and C3d - if complement activation continues past the C3 step, the membrane attack complex with C5b-C9 may form, which causes intravascular hemolysis. Sutimlimab is a humanized IgG4 monoclonal antibody targeted at the complement C1s subunit, a serine protease responsible for the activation of the classic complement pathway. By inhibiting the complement cascade at the level of C1s, sutimlimab prevents the deposition of complement opsinins on erythrocytes, thus preventing their eventual hemolysis. •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 at the approved weight-based recommended dosage, the exposure to sutimlimab increases proportionately with increasing dosage. Steady-state concentrations are achieved by week 7 of therapy. •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): At steady-state, the volume of distribution of sutimlimab in patients with cold agglutinin disease was approximately 5.8 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): As with other therapeutic proteins, sutimlimab likely undergoes catabolism 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): 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): At the approved recommended dosage, the terminal elimination half-life of sutimlimab is 21 days. The half-life of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •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 the approved recommended dosage, the clearance of sutimlimab is 0.14 L/day. The clearance of sutimlimab varies at different doses due to target-mediated drug disposition at lower concentrations. •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): Enjaymo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Sutimlimab •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): Sutimlimab is a monoclonal antibody directed towards complement subunit C1s used to reduce the need for blood transfusion due to hemolysis in patients with cold agglutinin disease. 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 Suvorexant interact?

•Drug A: Adalimumab •Drug B: Suvorexant •Severity: MODERATE •Description: The metabolism of Suvorexant 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): Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. •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): Suvorexant is a dual antagonist of orexin receptors OX1R and OX2R. It exerts its pharmacological effect by inhibiting binding of neuropeptides orexin A and B, also known as hypocretin 1 and 2, that are produced by neurons in the lateral hypothalamus. These neurons control the wake-promoting centers of the brain and are active during wakefulness, especially during motor activities, and stop firing during sleep. By inhibiting the reinforcement of arousal systems, suvorexant use causes a decrease in arousal and wakefulness, rather than having a direct sleep-promoting effect. •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): Peak concentrations occur at a median Tmax of 2 hours under fasted conditions. Ingestion of suvorexant with a high-fat meal has no effect on AUC or Cmax, but may delay Tmax by approximately 1.5 hours. Mean absolute bioavailability of 10 mg is 82%. •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): Mean volume of distribution is approximately 49 litres. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Suvorexant is extensively bound (>99%) to human plasma proteins and does not preferentially distribute into red blood cells. It binds to both human serum albumin and alpha1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Suvorexant is primarily metabolized by cytochrome-P450 3A4 enzyme (CYP3A4) with a minor contribution from CYP2C19. Major circulating metabolites are suvorexant and a hydroxy-suvorexant metabolite, which is not expected to be pharmacologically active. There is potential for drug-drug interactions with drugs that inhibit or induce CYP3A4 activity. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 66% is eliminated in feces and 23% is eliminated 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): Mean half life is approximately 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): Dose-related somnolence and CNS depression are the most common adverse effects associated with the use of suvorexant. It has also been shown to impair driving skills and may increase the risk of falling asleep while driving. Next-day impairments are found to be highest if suvorexant is taken with less than a full night of sleep remaining, with higher doses, or if co-administered with other CNS depressants or CYP3A inhibitors. Complex behaviours such as sleep driving, preparing and eating food, and making phone calls have been reported in association with the use of hypnotics such as suvorexant. A dose-dependant increase in suicidal ideation has been observed, especially in patients with a previous diagnosis of depression. Sleep paralysis, hypnagogic/hypnopompic hallucinations including vivid and disturbing perceptions, and mild cataplexy have also been reported. There are no adequate studies in pregnant women to ensure its safety during pregnancy or breast feeding. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Belsomra •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): Suvorexant is a orexin receptor antagonist used to treat insomnia that is characterized by difficulties with sleep onset and/or sleep maintenance.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Suvorexant interact? Information: •Drug A: Adalimumab •Drug B: Suvorexant •Severity: MODERATE •Description: The metabolism of Suvorexant 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): Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. •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): Suvorexant is a dual antagonist of orexin receptors OX1R and OX2R. It exerts its pharmacological effect by inhibiting binding of neuropeptides orexin A and B, also known as hypocretin 1 and 2, that are produced by neurons in the lateral hypothalamus. These neurons control the wake-promoting centers of the brain and are active during wakefulness, especially during motor activities, and stop firing during sleep. By inhibiting the reinforcement of arousal systems, suvorexant use causes a decrease in arousal and wakefulness, rather than having a direct sleep-promoting effect. •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): Peak concentrations occur at a median Tmax of 2 hours under fasted conditions. Ingestion of suvorexant with a high-fat meal has no effect on AUC or Cmax, but may delay Tmax by approximately 1.5 hours. Mean absolute bioavailability of 10 mg is 82%. •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): Mean volume of distribution is approximately 49 litres. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Suvorexant is extensively bound (>99%) to human plasma proteins and does not preferentially distribute into red blood cells. It binds to both human serum albumin and alpha1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Suvorexant is primarily metabolized by cytochrome-P450 3A4 enzyme (CYP3A4) with a minor contribution from CYP2C19. Major circulating metabolites are suvorexant and a hydroxy-suvorexant metabolite, which is not expected to be pharmacologically active. There is potential for drug-drug interactions with drugs that inhibit or induce CYP3A4 activity. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 66% is eliminated in feces and 23% is eliminated 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): Mean half life is approximately 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): Dose-related somnolence and CNS depression are the most common adverse effects associated with the use of suvorexant. It has also been shown to impair driving skills and may increase the risk of falling asleep while driving. Next-day impairments are found to be highest if suvorexant is taken with less than a full night of sleep remaining, with higher doses, or if co-administered with other CNS depressants or CYP3A inhibitors. Complex behaviours such as sleep driving, preparing and eating food, and making phone calls have been reported in association with the use of hypnotics such as suvorexant. A dose-dependant increase in suicidal ideation has been observed, especially in patients with a previous diagnosis of depression. Sleep paralysis, hypnagogic/hypnopompic hallucinations including vivid and disturbing perceptions, and mild cataplexy have also been reported. There are no adequate studies in pregnant women to ensure its safety during pregnancy or breast feeding. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Belsomra •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): Suvorexant is a orexin receptor antagonist used to treat insomnia that is characterized by difficulties with sleep onset and/or sleep maintenance. 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 Synthetic Conjugated Estrogens, A interact?

•Drug A: Adalimumab •Drug B: Synthetic Conjugated Estrogens, A •Severity: MINOR •Description: Synthetic Conjugated Estrogens, A may increase the thrombogenic activities of Adalimumab. •Extended Description: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. •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 moderate to severe vasomotor symptoms due to menopause and for treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. •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): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •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): Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several 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 of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate 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 half life of baseline-corrected estrone and equilin was found to be 10.6 hr and 9.7 hr, 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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cenestin •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): Synthetic Conjugated Estrogens, A is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal atrophy and dyspareunia.

Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. The severity of the interaction is minor.

Question: Does Adalimumab and Synthetic Conjugated Estrogens, A interact? Information: •Drug A: Adalimumab •Drug B: Synthetic Conjugated Estrogens, A •Severity: MINOR •Description: Synthetic Conjugated Estrogens, A may increase the thrombogenic activities of Adalimumab. •Extended Description: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. •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 moderate to severe vasomotor symptoms due to menopause and for treatment of moderate to severe symptoms of vulvar and vaginal atrophy due to menopause. •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): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •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): Synthetic conjugated estrogens, A are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The Cenestin tablet releases the synthetic conjugated estrogens, A slowly over a period of several 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 of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant portion of the circulating estrogens exist as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate 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 half life of baseline-corrected estrone and equilin was found to be 10.6 hr and 9.7 hr, 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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Cenestin •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): Synthetic Conjugated Estrogens, A is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal atrophy and dyspareunia. Output: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. The severity of the interaction is minor.

Does Adalimumab and Synthetic Conjugated Estrogens, B interact?

•Drug A: Adalimumab •Drug B: Synthetic Conjugated Estrogens, B •Severity: MINOR •Description: Synthetic Conjugated Estrogens, B may increase the thrombogenic activities of Adalimumab. •Extended Description: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. •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 moderate to severe vasomotor symptoms due to menopause and for the treatment of moderate to severe vaginal dryness, pain with intercourse, and symptoms of vulvar and vaginal atrophy due to menopause. •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): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •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): Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The tablets release synthetic conjugated estrogens, B slowly over a period of several 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 of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate 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 half life of baseline-corrected estrone and equilin was found to be 23.46 hr and 15.09 hr, 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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Enjuvia •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): Synthetic Conjugated Estrogens, B is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal dryness.

Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. The severity of the interaction is minor.

Question: Does Adalimumab and Synthetic Conjugated Estrogens, B interact? Information: •Drug A: Adalimumab •Drug B: Synthetic Conjugated Estrogens, B •Severity: MINOR •Description: Synthetic Conjugated Estrogens, B may increase the thrombogenic activities of Adalimumab. •Extended Description: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. •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 moderate to severe vasomotor symptoms due to menopause and for the treatment of moderate to severe vaginal dryness, pain with intercourse, and symptoms of vulvar and vaginal atrophy due to menopause. •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): All estrogen products mimic the effects of endogenous estrogens in the body which are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estrogens act by binding to estrogen receptors on a wide variety of tissues in the body and modulating the pituitary secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) through a negative feedback mechanism. Prior to menopause, the primary source of estrogen is the ovarian follicle, which secretes 70-500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. However, once a woman stops ovulating there is a sharp decline in the production of progesterone and estradiol by the ovaries and a consequent fluctuation in LH and FSH due to a lack of feedback control. This shift in hormone production is largely responsible for many of the symptoms experienced during and after menopause and includes hot flashes and other vasomotor symptoms, painful intercourse, vaginal dryness, and vulvovaginal atrophy. These symptoms are able to be reduced by replacing many of the hormones lost during and following menopause with synthetic or naturally occurring forms, in a therapy known as Hormone Replacement Therapy (HRT). •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): Synthetic conjugated estrogens, B are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. The tablets release synthetic conjugated estrogens, B slowly over a period of several 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 of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Exogenous estrogens are metabolized in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption. In postmenopausal women, a significant portion of the circulating estrogens exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogens. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Estradiol, estrone, and estriol are excreted in the urine along with glucuronide and sulfate 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 half life of baseline-corrected estrone and equilin was found to be 23.46 hr and 15.09 hr, 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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Enjuvia •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): Synthetic Conjugated Estrogens, B is a mixture of estrogens used to treat a variety of postmenopausal symptoms, including vaginal dryness. Output: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. The severity of the interaction is minor.

Does Adalimumab and Tacrolimus interact?

•Drug A: Adalimumab •Drug B: Tacrolimus •Severity: MODERATE •Description: Tacrolimus may increase the immunosuppressive activities of Adalimumab. •Extended Description: Tacrolimus is an immunosuppressant with a potential to induce infections, lymphoma and other malignancies, particularly with long-term use. The concomitant use of tacrolimus with other immunosuppressive agents may create an additive effect and lead to an increased risk of immunosuppression-related adverse reactions. •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): Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants, and may be used in patients converted from immediate-release formulations. Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable. Both available strengths are indicated in adult patients, while only the lower strength (0.03%) formulation is indicated in pediatric patients between 2 and 15 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): Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better 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): The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells. •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 tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. •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): 2.6 ± 2.1 L/kg [pediatric liver transplant patients] 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%. •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 in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) 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): 0.040 L/hr/kg [healthy subjects, IV] 0.172 ± 0.088 L/hr/kg [healthy subjects, oral] 0.083 L/hr/kg [adult kidney transplant patients, IV] 0.053 L/hr/kg [adult liver transplant patients, IV] 0.051 L/hr/kg [adult heart transplant patients, IV] 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients] 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients] 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO] •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): Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD 50 =134-194 mg/kg (rat). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Advagraf, Astagraf, Envarsus, Modigraf, Prograf, Protopic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tacrolimus •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): Tacrolimus is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis.

Tacrolimus is an immunosuppressant with a potential to induce infections, lymphoma and other malignancies, particularly with long-term use. The concomitant use of tacrolimus with other immunosuppressive agents may create an additive effect and lead to an increased risk of immunosuppression-related adverse reactions. The severity of the interaction is moderate.

Question: Does Adalimumab and Tacrolimus interact? Information: •Drug A: Adalimumab •Drug B: Tacrolimus •Severity: MODERATE •Description: Tacrolimus may increase the immunosuppressive activities of Adalimumab. •Extended Description: Tacrolimus is an immunosuppressant with a potential to induce infections, lymphoma and other malignancies, particularly with long-term use. The concomitant use of tacrolimus with other immunosuppressive agents may create an additive effect and lead to an increased risk of immunosuppression-related adverse reactions. •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): Immediate-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving allogeneic liver, kidney, heart, or lung transplants, in combination with other immunosuppressants. Extended-release formulations of tacrolimus are indicated for the prophylaxis of organ rejection in adult and pediatric patients receiving kidney transplants, in combination with other immunosuppressants, and may be used in patients converted from immediate-release formulations. Topical tacrolimus ointment is indicated as second-line therapy for short-term and non-continuous treatment of moderate-to-severe atopic dermatitis in non-immunocompromised adults and children who have failed to respond adequately to other topical treatments or for whom alternative treatments are not advisable. Both available strengths are indicated in adult patients, while only the lower strength (0.03%) formulation is indicated in pediatric patients between 2 and 15 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): Tacrolimus acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Tacrolimus has similar activity to cyclosporine but rates of rejection are lower with tacrolimus. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better 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): The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells. •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 tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition. •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): 2.6 ± 2.1 L/kg [pediatric liver transplant patients] 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO] •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): ~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of tacrolimus is predominantly mediated by CYP3A4 and secondarily by CYP3A5. Tacrolimus is metabolized into 8 metabolites: 13-demethyl tacrolimus, 31-demethyl tacrolimus, 15-demethyl tacrolimus, 12-hydroxy tacrolimus, 15,31-didemethyl tacrolimus, 13,31-didemethyl tacrolimus, 13,15-didemethyl tacrolimus, and a final metabolite involving O-demethylation and the formation of a fused ring. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%. •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 in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) 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): 0.040 L/hr/kg [healthy subjects, IV] 0.172 ± 0.088 L/hr/kg [healthy subjects, oral] 0.083 L/hr/kg [adult kidney transplant patients, IV] 0.053 L/hr/kg [adult liver transplant patients, IV] 0.051 L/hr/kg [adult heart transplant patients, IV] 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients] 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients] 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO] •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): Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion. LD 50 =134-194 mg/kg (rat). •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Advagraf, Astagraf, Envarsus, Modigraf, Prograf, Protopic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tacrolimus •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): Tacrolimus is a calcineurin inhibitor used to prevent organ transplant rejection and to treat moderate to severe atopic dermatitis. Output: Tacrolimus is an immunosuppressant with a potential to induce infections, lymphoma and other malignancies, particularly with long-term use. The concomitant use of tacrolimus with other immunosuppressive agents may create an additive effect and lead to an increased risk of immunosuppression-related adverse reactions. The severity of the interaction is moderate.

Does Adalimumab and Tadalafil interact?

•Drug A: Adalimumab •Drug B: Tadalafil •Severity: MODERATE •Description: The metabolism of Tadalafil 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): Tadalafil is indicated for the treatment of erectile dysfunction (ED) and either alone or in combination with finasteride for the treatment of benign prostatic hypertrophy (BPH). It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with macitentan or other endothelin-1 antagonists. •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): Tadalafil exerts a therapeutic effect in ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries. In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH. The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side 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): Tadalafil is a selective phosphodiesterase-5 (PDE5) inhibitor that produces several downstream effects with the most common therapeutic effect being smooth muscle relaxation. Patients may experience ED due to a variety of causes including psychogenic, neurogenic, vasculogenic, iatrogenic, or endocrine. These causes result in dysfunction of penile smooth muscle relaxation through either disrupted neuronal signaling or direct influence on smooth muscle cells. During sexual arousal, non-adrenergic non-cholinergic (NANC) neurons release nitric oxide (NO). Nitric oxide stimulates guanylate cyclase which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). cGMP activates the cGMP-dependent kinase (PKG) in a signal cascade which activates K+ channels leading to inhibition of Ca2+ channels, inhibits platelet activation, and inhibits smooth muscle cell proliferation while inducing apoptosis. This signal cascade is attenuated by PDE5 which breaks the phosphodiester bond of cGMP, converting it to GMP. Inhibition of PDE5 by tadalafil increases signaling via the PKG cascade which supports penile smooth muscle relaxation during sexual arousal by decreasing Ca2+ entry into smooth muscle cells. This smooth muscle relaxation allows blood to fill the corpus cavernosum thereby producing an erection. In PAH, blood pressure in the pulmonary arteries is raised due to a variety of mechanisms stemming from endothelial dysfunction. Decreased production of NO and prostacyclin reduce vasodilatory signaling while overproduction of endothelin-1 and thromboxane increase vasoconstriction. Inflammation, thromboses, and hypoxia later contribute to vascular remodeling which further reduces luminal size. The resultant increase in blood pressure reduces the capacity for gas exchange and increases afterload at the right ventricle, producing symptoms of dyspnea, fatigue, and dizziness as well as leading to right-sided heart failure. Tadalafil exerts its therapeutic effect in PAH through boosting NO-cGMP signaling to contribute to smooth muscle relaxation as with ED. Lastly, tadalafil is used to treat BPH. BPH produces urinary dysfunction through hyperproliferation of the epithelial and smooth muscle layers of the prostate. The increased size of the prostate blocks urine flow through the urethra resulting in higher residual volumes due to incomplete emptying. Tadalafil does not appear to exert its benefit via smooth muscle relaxation of the prostate. It may instead exert its effect through a mix of increased oxygenation and decreased inflammation, which decreases tissue remodeling, and inhibition of cell proliferation through the cGMP cascade. The decreased affinity for PDE6 compared to other PDE5 inhibitors may explain the decreased incidence of visual side effects as PDE6 is present in the eye and contributes to color vision. •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): Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. The tmax in adults with PAH is reported as 2-8h with a median of 4h. There does not appear to be a significant effect on absorption when tadalafil is 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): Tadalafil has a mean apparent volume of distribution of 63L in healthy adults. The mean apparent volume of distribution is reported as 77L in adults with PAH. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tadalafil is 94% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tadalafil undergoes hepatic metabolism via CYP3A4 to a catechol metabolite. This catechol metabolite undergoes subsequent methylation and glucuronidation with the methyl-glucuronide metabolite becoming the primary metabolite in circulation. None of the known metabolites are considered to be active. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tadalafil is primarily eliminated via hepatic metabolism. These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%) •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 half-life of elimination of tadalafil is 15-17.5h in healthy adults. The mean half-life of elimination in adults with PAH is reported as 35h. •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 mean apparent oral clearance of tadalafil is 2.5-3.4L/h in healthy adults. The mean apparent oral clearance in adults with PAH is reported as 3.5L/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): Symptoms of overdose are expected to be similar to typical adverse effects which may include headache, dyspepsia, back pain, myalgia, nasopharyngitis, and dizziness. Standard supportive care is recommended. Hemodialysis is not expected to contribute significantly to tadalafil clearance. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Adcirca, Alyq, Cialis, Entadfi, Tadliq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tadalafil Tadalafilo •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): Tadalafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tadalafil interact? Information: •Drug A: Adalimumab •Drug B: Tadalafil •Severity: MODERATE •Description: The metabolism of Tadalafil 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): Tadalafil is indicated for the treatment of erectile dysfunction (ED) and either alone or in combination with finasteride for the treatment of benign prostatic hypertrophy (BPH). It is also indicated for the treatment of pulmonary arterial hypertension (PAH) both alone and in combination with macitentan or other endothelin-1 antagonists. •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): Tadalafil exerts a therapeutic effect in ED by increasing sexual stimulation-dependant smooth muscle relaxation in the penis, allowing the corpus cavernosum to fill with blood to produce an erection. Smooth muscle relaxation in the pulmonary vasculature helps to produce vasodilation in PAH which reduces blood pressure in the pulmonary arteries. In BPH, tadalafil may contribute to decreased smooth muscle cell proliferation which may reduce the size of the prostate and relieve the anatomical obstruction which produces urinary symptoms of BPH. The decreased affinity of tadalafil for PDE6 compared to other PDE5 inhibitors may explain the reduced incidence of visual side 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): Tadalafil is a selective phosphodiesterase-5 (PDE5) inhibitor that produces several downstream effects with the most common therapeutic effect being smooth muscle relaxation. Patients may experience ED due to a variety of causes including psychogenic, neurogenic, vasculogenic, iatrogenic, or endocrine. These causes result in dysfunction of penile smooth muscle relaxation through either disrupted neuronal signaling or direct influence on smooth muscle cells. During sexual arousal, non-adrenergic non-cholinergic (NANC) neurons release nitric oxide (NO). Nitric oxide stimulates guanylate cyclase which converts guanosine triphosphate to cyclic guanosine monophosphate (cGMP). cGMP activates the cGMP-dependent kinase (PKG) in a signal cascade which activates K+ channels leading to inhibition of Ca2+ channels, inhibits platelet activation, and inhibits smooth muscle cell proliferation while inducing apoptosis. This signal cascade is attenuated by PDE5 which breaks the phosphodiester bond of cGMP, converting it to GMP. Inhibition of PDE5 by tadalafil increases signaling via the PKG cascade which supports penile smooth muscle relaxation during sexual arousal by decreasing Ca2+ entry into smooth muscle cells. This smooth muscle relaxation allows blood to fill the corpus cavernosum thereby producing an erection. In PAH, blood pressure in the pulmonary arteries is raised due to a variety of mechanisms stemming from endothelial dysfunction. Decreased production of NO and prostacyclin reduce vasodilatory signaling while overproduction of endothelin-1 and thromboxane increase vasoconstriction. Inflammation, thromboses, and hypoxia later contribute to vascular remodeling which further reduces luminal size. The resultant increase in blood pressure reduces the capacity for gas exchange and increases afterload at the right ventricle, producing symptoms of dyspnea, fatigue, and dizziness as well as leading to right-sided heart failure. Tadalafil exerts its therapeutic effect in PAH through boosting NO-cGMP signaling to contribute to smooth muscle relaxation as with ED. Lastly, tadalafil is used to treat BPH. BPH produces urinary dysfunction through hyperproliferation of the epithelial and smooth muscle layers of the prostate. The increased size of the prostate blocks urine flow through the urethra resulting in higher residual volumes due to incomplete emptying. Tadalafil does not appear to exert its benefit via smooth muscle relaxation of the prostate. It may instead exert its effect through a mix of increased oxygenation and decreased inflammation, which decreases tissue remodeling, and inhibition of cell proliferation through the cGMP cascade. The decreased affinity for PDE6 compared to other PDE5 inhibitors may explain the decreased incidence of visual side effects as PDE6 is present in the eye and contributes to color vision. •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): Tadalafil has a tmax of 0.5-6h with a median of 2h in healthy adults. The tmax in adults with PAH is reported as 2-8h with a median of 4h. There does not appear to be a significant effect on absorption when tadalafil is 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): Tadalafil has a mean apparent volume of distribution of 63L in healthy adults. The mean apparent volume of distribution is reported as 77L in adults with PAH. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tadalafil is 94% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tadalafil undergoes hepatic metabolism via CYP3A4 to a catechol metabolite. This catechol metabolite undergoes subsequent methylation and glucuronidation with the methyl-glucuronide metabolite becoming the primary metabolite in circulation. None of the known metabolites are considered to be active. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tadalafil is primarily eliminated via hepatic metabolism. These metabolites are mainly excreted in the feces (61%) and to a lesser extent in the urine (36%) •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 half-life of elimination of tadalafil is 15-17.5h in healthy adults. The mean half-life of elimination in adults with PAH is reported as 35h. •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 mean apparent oral clearance of tadalafil is 2.5-3.4L/h in healthy adults. The mean apparent oral clearance in adults with PAH is reported as 3.5L/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): Symptoms of overdose are expected to be similar to typical adverse effects which may include headache, dyspepsia, back pain, myalgia, nasopharyngitis, and dizziness. Standard supportive care is recommended. Hemodialysis is not expected to contribute significantly to tadalafil clearance. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Adcirca, Alyq, Cialis, Entadfi, Tadliq •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tadalafil Tadalafilo •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): Tadalafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction, benign prostatic hyperplasia, and pulmonary arterial hypertension. 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 Tafasitamab interact?

•Drug A: Adalimumab •Drug B: Tafasitamab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tafasitamab. •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): Tafasitamab is indicated, in combination with lenalidomide, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified whom are ineligible for autologous stem cell transplant (ASCT). •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): Tafasitamab induces a reduction in circulating B-cell counts by binding to a surface antigen, CD19, which is important for their survival. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) experienced a 97% reduction in peripheral blood B-cell counts following 8 days of treatment, with a 100% reduction reached within 16 weeks of treatment. Tafasitamab can cause infusion-related reactions, particularly during the initial cycles of therapy. Symptoms may include chills, flushing, dyspnea, and hypertension. Patients may be administered premedications (such as acetaminophen, antihistamines, or glucocorticoids) 0.5 - 2 hours prior to infusion to minimize infusion-related reactions. Tafasitamab may also cause significant myelosuppression, and subsequent infection, due to its mechanism of action - patients should undergo monitoring throughout therapy for signs of myelosuppression and/or infection. •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 CD19 surface antigen is a protein expressed on the surface of pre-B and mature B-lymphocytes that appears to play a role in enhancing B-cell receptor signaling and is considered integral to their survival. These surface proteins are also highly expressed on several B-cell malignancies, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and diffuse large B-cell lymphoma (DLBCL). Tafasitamab is a CD19-directed cytolytic monoclonal antibody that, upon binding and blocking the activity of CD19, causes lysis of B-cells. This process is mediated through both direct apoptosis and immune-mediated effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). •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 intravenous administration of tafasitamab 12 mg/kg on Days 1, 8, 15, and 22 in cycle(s) 1-3 (with an additional dose on Day 4 of cycle 1), mean trough concentrations were 179 (± 53) μg/mL. From cycle 4 onwards, which involve the administration of tafasitamab 12 mg/kg on Days 1 and 15, mean trough concentrations were 153 (± 68) μg/mL. The overall maximum tafasitamab serum concentrations reached were 483 (± 109) 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 total volume of distribution of tafasitamab following intravenous injection is approximately 9.3 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): The biotransformation of tafasitamab has not been elucidated. Most monoclonal antibodies undergo intracellular catabolism via lysosomal degradation to smaller amino acids and peptides. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions. •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 tafasitamab is approximately 17 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 tafasitamab is approximately 0.41 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): Data regarding overdose of tafasitamab are unavailable. Symptoms of overdosage are likely to be consistent with its adverse effect profile, and may therefore involve significant infusion-related reactions and/or myelosuppression. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Monjuvi •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): Tafasitamab is a CD19-directed cytolytic monoclonal antibody used in the treatment of B-cell malignancies.

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 Tafasitamab interact? Information: •Drug A: Adalimumab •Drug B: Tafasitamab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tafasitamab. •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): Tafasitamab is indicated, in combination with lenalidomide, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified whom are ineligible for autologous stem cell transplant (ASCT). •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): Tafasitamab induces a reduction in circulating B-cell counts by binding to a surface antigen, CD19, which is important for their survival. Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) experienced a 97% reduction in peripheral blood B-cell counts following 8 days of treatment, with a 100% reduction reached within 16 weeks of treatment. Tafasitamab can cause infusion-related reactions, particularly during the initial cycles of therapy. Symptoms may include chills, flushing, dyspnea, and hypertension. Patients may be administered premedications (such as acetaminophen, antihistamines, or glucocorticoids) 0.5 - 2 hours prior to infusion to minimize infusion-related reactions. Tafasitamab may also cause significant myelosuppression, and subsequent infection, due to its mechanism of action - patients should undergo monitoring throughout therapy for signs of myelosuppression and/or infection. •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 CD19 surface antigen is a protein expressed on the surface of pre-B and mature B-lymphocytes that appears to play a role in enhancing B-cell receptor signaling and is considered integral to their survival. These surface proteins are also highly expressed on several B-cell malignancies, such as chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and diffuse large B-cell lymphoma (DLBCL). Tafasitamab is a CD19-directed cytolytic monoclonal antibody that, upon binding and blocking the activity of CD19, causes lysis of B-cells. This process is mediated through both direct apoptosis and immune-mediated effector mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). •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 intravenous administration of tafasitamab 12 mg/kg on Days 1, 8, 15, and 22 in cycle(s) 1-3 (with an additional dose on Day 4 of cycle 1), mean trough concentrations were 179 (± 53) μg/mL. From cycle 4 onwards, which involve the administration of tafasitamab 12 mg/kg on Days 1 and 15, mean trough concentrations were 153 (± 68) μg/mL. The overall maximum tafasitamab serum concentrations reached were 483 (± 109) 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 total volume of distribution of tafasitamab following intravenous injection is approximately 9.3 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): The biotransformation of tafasitamab has not been elucidated. Most monoclonal antibodies undergo intracellular catabolism via lysosomal degradation to smaller amino acids and peptides. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Monoclonal antibodies are typically eliminated via uptake into cells and subsequent catabolism via lysosomal degradation. Due to their large size, they are only eliminated renally under pathologic conditions. •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 tafasitamab is approximately 17 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 tafasitamab is approximately 0.41 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): Data regarding overdose of tafasitamab are unavailable. Symptoms of overdosage are likely to be consistent with its adverse effect profile, and may therefore involve significant infusion-related reactions and/or myelosuppression. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Monjuvi •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): Tafasitamab is a CD19-directed cytolytic monoclonal antibody used in the treatment of B-cell malignancies. 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 Tafenoquine interact?

•Drug A: Adalimumab •Drug B: Tafenoquine •Severity: MODERATE •Description: The metabolism of Tafenoquine 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): Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria. Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by Plasmodium vivax, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses. •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 that tafenoquine presents an average 50% inhibitory concentration of 0.436 mcg against blood stages of seven strains of P. falciparum. In chloroquine-resistant P. falciparum strains the IC50 of tafenoquine was greater when compared with primaquine and it ranged from 0.5 to 33.1 mcg. In studies evaluating the transmission-blocking activity of tafenoquine against the sporogonic stage of P. vivax, it was showed a reduced transmission at doses higher than 25 mg/kg. In clinical trials, it was reported a tafenoquine-induced relapse prevention of 91.9% in cases of vivax malaria when pretreated with chloroquine. In prophylactic studies, tafenoquine showed an efficacy range from 84 to 87% against falciparum malaria and 99.1% against vivax malaria. •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 tafenoquine is not well established but studies have reported a longer and more effective action when compared to primaquine. The active moiety of tafenoquine, 5,6 ortho quinone tafenoquine, seems to be redox cycled by P. falciparum which are upregulated in gametocytes and liver stages. Once inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl radicals. It is thought that these radicals produce leads to the parasite death. On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites. •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 first-in-human pharmacokinetic study showed a tmax of 13.8 hours and this study suggested that the prolonged absorption from the gut can be due to absorption in the distal gastrointestinal tract combined with a slow clearance. The AUC and Cmax demonstrated an intersubject variability. The bioavailability of tafenoquine is increased in the presence of a high-fat meal by modifying the amount of drug absorbed rather than the rate of absorption. Once absorbed, the concentration of tafenoquine in the whole body is two-fold higher than the corresponding concentration in plasma and it seems to be highly distributed in the liver showing an AUC of approximately 80 times more than what is found in the plasma. •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): Tafenoquine presents a high volume of distribution of approximately 2 560 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of tafenoquine in humans is very high and it represents about 99.5%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. This activation step produces the metabolite 5,6 ortho quinone tafenoquine. This metabolite is internalized by the parasite and reduced to radicals by ferredoxin-NADP+ reductase and diflavin reductase enzymes. In the human, tafenoquine is metabolized by several metabolic pathways including O-demethylation, N-dealkylation, N-oxidation and oxidative deamination as well as C-hydroxylation of the 8-aminoalkylamino side chain. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After degradation by different metabolic pathways, tafenoquine is slowly excreted from the body primarily in the feces and renal elimination of the unchanged form is very 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): Tafenoquine presents a long half-life of approximately 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): Tafenoquine presents a low clearance of approximately 6 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): Tafenoquine can cause hemolysis in people with glucose-6-phosphate dehydrogenase deficiency. In preclinical studies, renal cell adenomas and carcinomas are increased in male rats with an overdose administration. However, this drug does not seem to be carcinogenic in humans and it was shown to lack mutagenic potential. In fertility studies, tafenoquine resulted in a reduced number of viable fetuses, implantation sites and corpora lutea. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Arakoda, Krintafel •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): Tafenoquine is an antiparasitic agent used for the treatment and prevention of relapse of Vivax malaria.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tafenoquine interact? Information: •Drug A: Adalimumab •Drug B: Tafenoquine •Severity: MODERATE •Description: The metabolism of Tafenoquine 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): Tafenoquine is used for the treatment and prevention of relapse of Vivax malaria in patients 16 years and older. Tafenoquine is not indicated to treat acute vivax malaria. Malaria is a disease that remains to occur in many tropical countries. Vivax malaria, caused by Plasmodium vivax, is known to be less virulent and seldom causes death. However, it causes a substantive illness-related burden in endemic areas and it is known to present dormant forms in the hepatocytes named hypnozoites which can remain dormant for weeks or even months. This dormant form produces ongoing relapses. •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 that tafenoquine presents an average 50% inhibitory concentration of 0.436 mcg against blood stages of seven strains of P. falciparum. In chloroquine-resistant P. falciparum strains the IC50 of tafenoquine was greater when compared with primaquine and it ranged from 0.5 to 33.1 mcg. In studies evaluating the transmission-blocking activity of tafenoquine against the sporogonic stage of P. vivax, it was showed a reduced transmission at doses higher than 25 mg/kg. In clinical trials, it was reported a tafenoquine-induced relapse prevention of 91.9% in cases of vivax malaria when pretreated with chloroquine. In prophylactic studies, tafenoquine showed an efficacy range from 84 to 87% against falciparum malaria and 99.1% against vivax malaria. •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 tafenoquine is not well established but studies have reported a longer and more effective action when compared to primaquine. The active moiety of tafenoquine, 5,6 ortho quinone tafenoquine, seems to be redox cycled by P. falciparum which are upregulated in gametocytes and liver stages. Once inside, the oxidated metabolite produces hydrogen peroxide and hydroxyl radicals. It is thought that these radicals produce leads to the parasite death. On the other hand, tafenoquine inhibits heme polymerase in blood stage of parasites which explains the activity against blood stages of parasites. •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 first-in-human pharmacokinetic study showed a tmax of 13.8 hours and this study suggested that the prolonged absorption from the gut can be due to absorption in the distal gastrointestinal tract combined with a slow clearance. The AUC and Cmax demonstrated an intersubject variability. The bioavailability of tafenoquine is increased in the presence of a high-fat meal by modifying the amount of drug absorbed rather than the rate of absorption. Once absorbed, the concentration of tafenoquine in the whole body is two-fold higher than the corresponding concentration in plasma and it seems to be highly distributed in the liver showing an AUC of approximately 80 times more than what is found in the plasma. •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): Tafenoquine presents a high volume of distribution of approximately 2 560 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of tafenoquine in humans is very high and it represents about 99.5%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The activation of tafenoquine needs the activity of CYP 2D6 liver microsomal enzyme. This activation step produces the metabolite 5,6 ortho quinone tafenoquine. This metabolite is internalized by the parasite and reduced to radicals by ferredoxin-NADP+ reductase and diflavin reductase enzymes. In the human, tafenoquine is metabolized by several metabolic pathways including O-demethylation, N-dealkylation, N-oxidation and oxidative deamination as well as C-hydroxylation of the 8-aminoalkylamino side chain. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After degradation by different metabolic pathways, tafenoquine is slowly excreted from the body primarily in the feces and renal elimination of the unchanged form is very 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): Tafenoquine presents a long half-life of approximately 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): Tafenoquine presents a low clearance of approximately 6 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): Tafenoquine can cause hemolysis in people with glucose-6-phosphate dehydrogenase deficiency. In preclinical studies, renal cell adenomas and carcinomas are increased in male rats with an overdose administration. However, this drug does not seem to be carcinogenic in humans and it was shown to lack mutagenic potential. In fertility studies, tafenoquine resulted in a reduced number of viable fetuses, implantation sites and corpora lutea. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Arakoda, Krintafel •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): Tafenoquine is an antiparasitic agent used for the treatment and prevention of relapse of Vivax malaria. 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 Tamoxifen interact?

•Drug A: Adalimumab •Drug B: Tamoxifen •Severity: MAJOR •Description: The metabolism of Tamoxifen 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): Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ. •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): Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies. •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): Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth. Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β. •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): An oral dose of 20mg reaches a C max of 40ng/mL with a T max of 5 hours. The metabolite N-desmethyltamoxifen reaches a C max of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a C ss of 120ng/mL and a C ss of 336ng/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 tamoxifen is approximately 50-60L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of tamoxifen in plasma is over 98% and mostly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% 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 elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 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 of tamoxifen was 189mL/min in a study of six postmenopausal women. •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): High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Soltamox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tamoxifen Tamoxifène Tamoxifene Tamoxifeno Tamoxifenum trans-Tamoxifen •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): Tamoxifen is a selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tamoxifen interact? Information: •Drug A: Adalimumab •Drug B: Tamoxifen •Severity: MAJOR •Description: The metabolism of Tamoxifen 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): Tamoxifen is indicated to treat estrogen receptor positive metastatic breast cancer in adults, as an adjuvant in the treatment of early stage estrogen receptor positive breast cancer in adults, to reduce the risk of invasive breast cancer after surgery and radiation in adult women with ductal carcinoma in situ. •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): Tamoxifen is a selective estrogen receptor modulator that inhibits growth and promotes apoptosis in estrogen receptor positive tumors. It has a long duration of action as the active metabolite N-desmethyltamoxifen has a half life of approximately 2 weeks. It has a narrow therapeutic index as higher doses can lead to breathing difficulty or convulsions. Tamoxifen administration is also associated with an increased incidence of uterine malignancies. •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): Tamoxifen competitively inhibits estrogen binding to its receptor, which is critical for it's activity in breast cancer cells. Tamoxifen leads to a decrease in tumor growth factor α and insulin-like growth factor 1, and an increase in sex hormone binding globulin. The increase in sex hormon binding globulin limits the amount of freely available estradiol. These changes reduce levels of factors that stimulate tumor growth. Tamoxifen has also been shown to induce apoptosis in estrogen receptor positive cells. This action is thought to be the result of inhibition of protein kinase C, which prevents DNA synthesis. Alternate theories for the apoptotic effect of tamoxifen comes from the approximately 3 fold increase in intracellular and mitochondrial calcium ion levels after administration or the induction of tumor growth factor β. •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): An oral dose of 20mg reaches a C max of 40ng/mL with a T max of 5 hours. The metabolite N-desmethyltamoxifen reaches a C max of 15ng/mL. 10mg of tamoxifen orally twice daily for 3 months results in a C ss of 120ng/mL and a C ss of 336ng/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 tamoxifen is approximately 50-60L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding of tamoxifen in plasma is over 98% and mostly to serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tamoxifen can by hydroxylated to α-hydroxytamoxifen which is then glucuronidated or undergoes sulfate conjugation by sulfotransferase 2A1. Tamoxifen can also undergo N-oxidation by flavin monooxygenases 1 and 3 to tamoxifen N-oxide. Tamoxifen is N-dealkylated to N-desmethyltamoxifen by CYP2D6, CYP1A1, CYP1A2, CYP3A4, CYP1B1, CYP2C9, CYP2C19, and CYP3A5. N-desmethyltamoxifen can be sulfate conjugated to form N-desmethyltamoxifen sulfate, 4-hydroxylated by CYP2D6 to form endoxifen, or N-dealkylated again by CYP3A4 and CYP3A5 to N,N-didesmethyltamoxifen. N,N-didesmethyltamoxifen undergoes a substitution reaction to form tamoxifen metabolite Y, followed by ether cleavage to metabolite E, which can then be sulfate conjugated by sulfotransferase 1A1 and 1E1 or O-glucuronidated. Tamoxifen can also by 4-hydroxylated by CYP2D6, CYP2B6, CYP3A4, CYP2C9, and CYP2C19 to form 4-hydroxytamoxifen. 4-hydroxytamoxifen can undergo glucuronidation by UGT1A8, UGT1A10, UGT2B7, and UGT2B17 to tamoxifen glucuronides, sulfate conjugation by sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, or N-dealkylation by CYP3A4 and CYP3A5 to endoxifen. Endoxifen undergoes demethylation to norendoxifen, a reversible sulfate conjugation reaction via sulfotransferase 1A1 and 1E1 to 4-hydroxytamoxifen sulfate, sulfate conjugation via sulfotransferase 2A1 to 4-endoxifen sulfate, or glucuronidation via UGT1A8, UGT1A10, UGT2B7, or UGT2B15 to tamoxifen glucuronides. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tamoxifen is mainly eliminated in the feces. Animal studies have shown 75% of radiolabelled tamoxifen recovered in the feces, with negligible collection from urine. However, 1 human study showed 26.7% recovery in the urine and 24.7% 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 elimination half-life of tamoxifen is 5 to 7 days, while the half-life of N-desmethyltamoxifen, the primary circulating metabolite, is approximately 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 of tamoxifen was 189mL/min in a study of six postmenopausal women. •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): High doses of tamoxifen in animals lead to respiratory difficulty and convulsions. High doses in advanced metastatic cancer patients resulted in acute neurotoxicity seen by tremor, hyperreflexia, unsteady gait, and dizziness. Patients experiencing and overdose should be given supportive treatment as no specific treatment for overdose is suggested. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Soltamox •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tamoxifen Tamoxifène Tamoxifene Tamoxifeno Tamoxifenum trans-Tamoxifen •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): Tamoxifen is a selective estrogen receptor modulator used to treat estrogen receptor positive breast cancer, reduce the risk of invasive breast cancer following surgery, or reduce the risk of breast cancer in high risk women. 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 Tamsulosin interact?

•Drug A: Adalimumab •Drug B: Tamsulosin •Severity: MODERATE •Description: The metabolism of Tamsulosin 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): Tamsulosin is indicated for the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin is also used off label for the treatment of ureteral stones, prostatitis, and female voiding dysfunction. •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): Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3.9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension. •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): Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas. •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 tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL*hr for a 0.4mg oral dose and 440-557ng/mL*hr for a 0.8mg oral dose. The maximum plasma concentration is 3.1-5.3ng/mL for a 0.4mg oral dose and 2.5-3.6ng/mL for a 0.8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%. •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): 16L after intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tamsulosin is 94%-99% protein bound, mostly to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tamsulosin is mostly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6, with some metabolism by other CYPs. CYP3A4 is responsible for the deethylation of tamsulosin to the M-1 metabolite and the oxidative deamination to the AM-1 metabolite, while CYP2D6 is responsible for the hydroxylation of tamsulosin to the M-3 metabolite and the demethylation of tamsulosin to the M-4 metabolite. In addition, tamsulosin can be hydroxylated at a different position by an unknown enzyme to form the M-2 metabolite. The M-1, M-2, M-3, and M-4 metabolites can be glucuronidated, and the M-1 and M-3 metabolites can undergo sulfate conjugation to form other metabolites before excretion. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8.7% of the dose is excreted as unmetabolized tamsulosin. •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 in fasted patients is 14.9±3.9 hours. The elimination half life is 5-7 hours and the apparent half life is 9 to 13 hours in healthy subjects. In patients who require tamsulosin, the apparent half life is 14-15 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): 2.88L/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): In the event of overdose, patients may experience hypotension and should lie down in a supine position to maintain blood pressure and heart rate. If further measures are required intravenous fluids should be considered. If further progression is required, vasopressors may be used and renal function should be monitored. Dialysis is unlikely to assist in treating overdose because tamsulosin is extensively protein bound. The oral LD50 in rats is 650mg/kg. Tamsulosin is not indicated for use in women and no studies have been performed in pregnancy, though animal studies have not shown fetal harm. Tamsulosin is excreted in the milk of rats but there is no available data on what the effect of this tamsulosin exposure may be. Animal studies have shown male and female rat fertility is affected by tamsulosin due to impairment of ejaculation and fertilization. In men, tamsulosin is associated with abnormal ejaculation. Tamsulosin is not mutagenic but may be carcinogenic at levels above the maximum recommended human dose. Female rats experience a slight increase in the rates of mammary gland fibroadenomas and adenocarcinomas. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Flomax, Jalyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tamsulosin Tamsulosina Tamsulosine Tamsulosinum •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): Tamsulosin is an alpha-1A and alpha-1B adrenergic receptor antagonist used to treat benign prostatic hyperplasia, ureteral stones, prostatitis, and female voiding dysfunction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tamsulosin interact? Information: •Drug A: Adalimumab •Drug B: Tamsulosin •Severity: MODERATE •Description: The metabolism of Tamsulosin 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): Tamsulosin is indicated for the treatment of signs and symptoms of benign prostatic hyperplasia. Tamsulosin is also used off label for the treatment of ureteral stones, prostatitis, and female voiding dysfunction. •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): Tamsulosin is an alpha adrenoceptor blocker with specificity for the alpha-1A and alpha-1D subtypes, which are more common in the prostate and submaxillary tissue. The final subtype, alpha-1B, are most common in the aorta and spleen. Tamsulosin binds to alpha-1A receptors 3.9-38 times more selectively than alpha-1B and 3-20 times more selectively than alpha-1D. This selectivity allows for a significant effect on urinary flow with a reduced incidence of adverse reactions like orthostatic hypotension. •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): Tamsulosin is a blocker of alpha-1A and alpha-1D adrenoceptors. About 70% of the alpha-1 adrenoceptors in the prostate are of the alpha-1A subtype. By blocking these adrenoceptors, smooth muscle in the prostate is relaxed and urinary flow is improved. The blocking of alpha-1D adrenoceptors relaxes the detrusor muscles of the bladder which prevents storage symptoms. The specificity of tamsulosin focuses the effects to the target area while minimizing effects in other areas. •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 tamsulosin is 90% absorbed in fasted patients. The area under the curve is 151-199ng/mL*hr for a 0.4mg oral dose and 440-557ng/mL*hr for a 0.8mg oral dose. The maximum plasma concentration is 3.1-5.3ng/mL for a 0.4mg oral dose and 2.5-3.6ng/mL for a 0.8mg oral dose. Taking tamsulosin with food increases the time to maximum concentration from 4-5 hours to 6-7 hours but increases bioavailability by 30% and maximum plasma concentration by 40-70%. •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): 16L after intravenous administration. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tamsulosin is 94%-99% protein bound, mostly to alpha-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tamsulosin is mostly metabolized in the liver by cytochrome P450 (CYP) 3A4 and 2D6, with some metabolism by other CYPs. CYP3A4 is responsible for the deethylation of tamsulosin to the M-1 metabolite and the oxidative deamination to the AM-1 metabolite, while CYP2D6 is responsible for the hydroxylation of tamsulosin to the M-3 metabolite and the demethylation of tamsulosin to the M-4 metabolite. In addition, tamsulosin can be hydroxylated at a different position by an unknown enzyme to form the M-2 metabolite. The M-1, M-2, M-3, and M-4 metabolites can be glucuronidated, and the M-1 and M-3 metabolites can undergo sulfate conjugation to form other metabolites before excretion. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 97% of an orally administered does is recovered in studies, which 76% in the urine and 21% in the feces after 168 hours. 8.7% of the dose is excreted as unmetabolized tamsulosin. •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 in fasted patients is 14.9±3.9 hours. The elimination half life is 5-7 hours and the apparent half life is 9 to 13 hours in healthy subjects. In patients who require tamsulosin, the apparent half life is 14-15 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): 2.88L/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): In the event of overdose, patients may experience hypotension and should lie down in a supine position to maintain blood pressure and heart rate. If further measures are required intravenous fluids should be considered. If further progression is required, vasopressors may be used and renal function should be monitored. Dialysis is unlikely to assist in treating overdose because tamsulosin is extensively protein bound. The oral LD50 in rats is 650mg/kg. Tamsulosin is not indicated for use in women and no studies have been performed in pregnancy, though animal studies have not shown fetal harm. Tamsulosin is excreted in the milk of rats but there is no available data on what the effect of this tamsulosin exposure may be. Animal studies have shown male and female rat fertility is affected by tamsulosin due to impairment of ejaculation and fertilization. In men, tamsulosin is associated with abnormal ejaculation. Tamsulosin is not mutagenic but may be carcinogenic at levels above the maximum recommended human dose. Female rats experience a slight increase in the rates of mammary gland fibroadenomas and adenocarcinomas. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Flomax, Jalyn •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tamsulosin Tamsulosina Tamsulosine Tamsulosinum •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): Tamsulosin is an alpha-1A and alpha-1B adrenergic receptor antagonist used to treat benign prostatic hyperplasia, ureteral stones, prostatitis, and female voiding dysfunction. 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 Tasimelteon interact?

•Drug A: Adalimumab •Drug B: Tasimelteon •Severity: MODERATE •Description: The metabolism of Tasimelteon 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): Tasimelteon oral capsules are indicated for the treatment of non-24 hour sleep-wake disorder in adult patients and for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome in patients ≥16 years old. Tasimelteon oral suspension is indicated for the treatment of nighttime sleep disturbances in Smith-Magenis syndrome in patients 3 to 15 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): 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): Tasimelteon is a selective dual agonist of the melatonin receptors MT1 and MT2. •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): The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 56 - 126 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At therapeutic concentrations, tasimelteon is about 90% bound to proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Phenolic glucuronidation is the major phase II metabolic route. •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 radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the 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 observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 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 are headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infections. There are currently no adequate or well-controlled studies that suggest that tasimelteon is safe to use during pregnancy. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. During clinical trials, rats did not self-administer tasimelteon, suggesting that the drug does not have a potential for abuse. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Hetlioz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tasimeltéon Tasimelteon Tasimelteón Tasimelteonum •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): Tasimelteon is a melatonin receptor agonist used to treat Non- 24-Hour Sleep-Wake 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. The severity of the interaction is moderate.

Question: Does Adalimumab and Tasimelteon interact? Information: •Drug A: Adalimumab •Drug B: Tasimelteon •Severity: MODERATE •Description: The metabolism of Tasimelteon 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): Tasimelteon oral capsules are indicated for the treatment of non-24 hour sleep-wake disorder in adult patients and for the treatment of nighttime sleep disturbances in Smith-Magenis Syndrome in patients ≥16 years old. Tasimelteon oral suspension is indicated for the treatment of nighttime sleep disturbances in Smith-Magenis syndrome in patients 3 to 15 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): 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): Tasimelteon is a selective dual agonist of the melatonin receptors MT1 and MT2. •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): The apparent oral volume of distribution of tasimelteon at steady state in young healthy subjects is approximately 56 - 126 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At therapeutic concentrations, tasimelteon is about 90% bound to proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tasimelteon is extensively metabolized. Metabolism of tasimelteon consists primarily of oxidation at multiple sites and oxidative dealkylation resulting in opening of the dihydrofuran ring followed by further oxidation to give a carboxylic acid. CYP1A2 and CYP3A4 are the major isozymes involved in the metabolism of tasimelteon. Phenolic glucuronidation is the major phase II metabolic route. •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 radiolabeled tasimelteon, 80% of total radioactivity was excreted in urine and approximately 4% in feces, resulting in a mean recovery of 84%. Less than 1% of the dose was excreted in urine as the 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 observed mean elimination half-life for tasimelteon is 1.3 ± 0.4 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 are headache, increased alanine aminotransferase, nightmares or unusual dreams, and upper respiratory or urinary tract infections. There are currently no adequate or well-controlled studies that suggest that tasimelteon is safe to use during pregnancy. In animal studies, administration of tasimelteon during pregnancy resulted in developmental toxicity (embryofetal mortality, neurobehavioral impairment, and decreased growth and development in offspring) at doses greater than those used clinically. During clinical trials, rats did not self-administer tasimelteon, suggesting that the drug does not have a potential for abuse. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Hetlioz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tasimeltéon Tasimelteon Tasimelteón Tasimelteonum •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): Tasimelteon is a melatonin receptor agonist used to treat Non- 24-Hour Sleep-Wake 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. The severity of the interaction is moderate.

Does Adalimumab and Tazarotene interact?

•Drug A: Adalimumab •Drug B: Tazarotene •Severity: MODERATE •Description: The metabolism of Tazarotene 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): Used to treat psoriasis, acne and sun damaged skin (photodamage). •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): Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. When treating acne tazarotene may be taken in conjunction with an oral antibiotic. Tazarotene has been shown in peer-reviewed double blinded studies to reduce: mottling and hyperpigmentation, sallowness, fine wrinkling and coarse wrinkling in sun damaged skin. Histological studies have shown that long term (greater than 1 year) use of Tazarotene is associated with a significant reduction in atypical melanocytes and keratocytes - cells considered to be precursors of skin cancer. Some studies have shown long term use of Tazarotene to be associated with increased collagen production and better organization of skin collagen bundles. •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 tazarotene action is not known, studies have shown that the active form of the drug (tazarotenic acid) binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARb, and RARg, but shows relative selectivity for RARb, and RARg and may modify gene expression. It also has affinity for RXR 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): Minimal systemic absorption of tazarotene occurs due to its rapid metabolism in the skin to the active metabolite, tazarotenic acid, which can be systemically absorbed and further metabolized. Gender had no influence on the systemic bioavailability of tazarotenic acid. •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 active form of the drug, tazarotenic acid, is highly bound to plasma proteins (>99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Undergoes esterase hydrolysis in skin to form its active metabolite, tazarotenic acid. Tazarotenic acid is further metabolized in skin and, after systemic absorption, hepatically metabolized to sulfoxides, sulfones, and other polar products for elimination. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. •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 active form of the drug, tazarotenic acid, is approximately 18 hours in normal and psoriatic patients. •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): Excessive topical use may lead to marked redness, peeling, or discomfort. Oral ingestion of the drug may affect liver function causing hypertriglyceridemia. Other symptoms may include conjunctival irritation, hair loss, headache, edema, fatigue, dermatitis, nausea, and visual disturbances. Oral administration of this material to rats and rabbits at doses of 0.20 mg/kg/day (rabbits) and 0.25 mg/kg/day (rats) resulted in developmental toxicity. A no effect level of 0.05 mg/kg/day was established. Similar teratogenic effects have been reported for other retinoid compounds. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Arazlo, Duobrii, Fabior, Tazorac •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): Tazarotene is an acetylenic retinoid used to treat fine wrinkles, mottled pigmentation of the skin, acne vulgaris, and plaque psoriasis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tazarotene interact? Information: •Drug A: Adalimumab •Drug B: Tazarotene •Severity: MODERATE •Description: The metabolism of Tazarotene 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): Used to treat psoriasis, acne and sun damaged skin (photodamage). •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): Following topical application, tazarotene undergoes esterase hydrolysis to form its active metabolite, tazarotenic acid. When treating acne tazarotene may be taken in conjunction with an oral antibiotic. Tazarotene has been shown in peer-reviewed double blinded studies to reduce: mottling and hyperpigmentation, sallowness, fine wrinkling and coarse wrinkling in sun damaged skin. Histological studies have shown that long term (greater than 1 year) use of Tazarotene is associated with a significant reduction in atypical melanocytes and keratocytes - cells considered to be precursors of skin cancer. Some studies have shown long term use of Tazarotene to be associated with increased collagen production and better organization of skin collagen bundles. •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 tazarotene action is not known, studies have shown that the active form of the drug (tazarotenic acid) binds to all three members of the retinoic acid receptor (RAR) family: RARa, RARb, and RARg, but shows relative selectivity for RARb, and RARg and may modify gene expression. It also has affinity for RXR 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): Minimal systemic absorption of tazarotene occurs due to its rapid metabolism in the skin to the active metabolite, tazarotenic acid, which can be systemically absorbed and further metabolized. Gender had no influence on the systemic bioavailability of tazarotenic acid. •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 active form of the drug, tazarotenic acid, is highly bound to plasma proteins (>99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Undergoes esterase hydrolysis in skin to form its active metabolite, tazarotenic acid. Tazarotenic acid is further metabolized in skin and, after systemic absorption, hepatically metabolized to sulfoxides, sulfones, and other polar products for elimination. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tazarotene and tazarotenic acid were metabolized to sulfoxides, sulfones and other polar metabolites which were eliminated through urinary and fecal pathways. •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 active form of the drug, tazarotenic acid, is approximately 18 hours in normal and psoriatic patients. •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): Excessive topical use may lead to marked redness, peeling, or discomfort. Oral ingestion of the drug may affect liver function causing hypertriglyceridemia. Other symptoms may include conjunctival irritation, hair loss, headache, edema, fatigue, dermatitis, nausea, and visual disturbances. Oral administration of this material to rats and rabbits at doses of 0.20 mg/kg/day (rabbits) and 0.25 mg/kg/day (rats) resulted in developmental toxicity. A no effect level of 0.05 mg/kg/day was established. Similar teratogenic effects have been reported for other retinoid compounds. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Arazlo, Duobrii, Fabior, Tazorac •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): Tazarotene is an acetylenic retinoid used to treat fine wrinkles, mottled pigmentation of the skin, acne vulgaris, and plaque psoriasis. 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 Tazemetostat interact?

•Drug A: Adalimumab •Drug B: Tazemetostat •Severity: MODERATE •Description: The metabolism of Tazemetostat 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): Tazemetostat is indicated to treat adult and pediatric patients 16 years and older with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection. It is also indicated to treat adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an IZH2 mutation and who have received at least 2 prior systemic therapies. Additionally, it is indicated in adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options. •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): Tazemetostat is a methyltransferase inhibitor that prevents hyper-trimethylation of histones and inhibits cancer cell de-differentiation. The duration of action is long as it is given twice daily. Patients should be counselled regarding the risk of secondary malignancies and embryo-fetal toxicity. •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): EZH2 is a methyltransferase subunit of the polycomb repressive complex 2 (PRC2) which catalyzes multiple methylations of lysine 27 on histone H3 (H3K27). Trimethylation of this lysine inhibits the transcription of genes associated with cell cycle arrest. PRC2 is antagonized by the switch/sucrose non-fermentable (SWI/SNF) multiprotein complex. Abnormal activation of EZH2 or loss of function mutations in SWI/SNF lead to hyper-trimethylation of H3K27. Hyper-trimethylation of H3K27 leads to cancer cell de-differentiation, a gain of cancer stem cell-like properties. De-differentiation can allow for cancer cell proliferation. Tazemetostat inhibits EZH2, preventing hyper-trimethylation of H3K27 and an uncontrollable cell cycle. •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): Tazemetostat 800mg twice daily leads to a C max of 829ng/mL, with a T max of 1-2 hours, and an AUC of 3340ng*h/mL. Absorption is not significantly affected by a high fat, high calorie meal. Tazemetostat is 33% bioavailable. •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): Tazemetostat has a volume of distribution of 1230L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tazemetostat is 88% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tazemetostat is metabolized by CYP3A4 to an inactive desethyl metabolite and one other inactive metabolite not described. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tazemetostat is 15% eliminated in urine and 79% eliminated 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): Tazemetostat has a terminal elimination half life of 3.1h. •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): Tazemetostat has an apparent total clearance of 274L/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): Data regarding the presentation and management of tazemetostat overdoses are not readily available. The most common adverse reactions associated with tazemetostat are pain, fatigue, nausea, decreased appetite, vomiting, and constipation. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tazverik •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): Tazemetostat is a methyltransferase inhibitor indicated to treat patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tazemetostat interact? Information: •Drug A: Adalimumab •Drug B: Tazemetostat •Severity: MODERATE •Description: The metabolism of Tazemetostat 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): Tazemetostat is indicated to treat adult and pediatric patients 16 years and older with metastatic or locally advanced epithelioid sarcoma that is not eligible for complete resection. It is also indicated to treat adult patients with relapsed or refractory follicular lymphoma whose tumors are positive for an IZH2 mutation and who have received at least 2 prior systemic therapies. Additionally, it is indicated in adult patients with relapsed or refractory follicular lymphoma who have no satisfactory alternative treatment options. •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): Tazemetostat is a methyltransferase inhibitor that prevents hyper-trimethylation of histones and inhibits cancer cell de-differentiation. The duration of action is long as it is given twice daily. Patients should be counselled regarding the risk of secondary malignancies and embryo-fetal toxicity. •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): EZH2 is a methyltransferase subunit of the polycomb repressive complex 2 (PRC2) which catalyzes multiple methylations of lysine 27 on histone H3 (H3K27). Trimethylation of this lysine inhibits the transcription of genes associated with cell cycle arrest. PRC2 is antagonized by the switch/sucrose non-fermentable (SWI/SNF) multiprotein complex. Abnormal activation of EZH2 or loss of function mutations in SWI/SNF lead to hyper-trimethylation of H3K27. Hyper-trimethylation of H3K27 leads to cancer cell de-differentiation, a gain of cancer stem cell-like properties. De-differentiation can allow for cancer cell proliferation. Tazemetostat inhibits EZH2, preventing hyper-trimethylation of H3K27 and an uncontrollable cell cycle. •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): Tazemetostat 800mg twice daily leads to a C max of 829ng/mL, with a T max of 1-2 hours, and an AUC of 3340ng*h/mL. Absorption is not significantly affected by a high fat, high calorie meal. Tazemetostat is 33% bioavailable. •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): Tazemetostat has a volume of distribution of 1230L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tazemetostat is 88% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tazemetostat is metabolized by CYP3A4 to an inactive desethyl metabolite and one other inactive metabolite not described. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tazemetostat is 15% eliminated in urine and 79% eliminated 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): Tazemetostat has a terminal elimination half life of 3.1h. •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): Tazemetostat has an apparent total clearance of 274L/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): Data regarding the presentation and management of tazemetostat overdoses are not readily available. The most common adverse reactions associated with tazemetostat are pain, fatigue, nausea, decreased appetite, vomiting, and constipation. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tazverik •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): Tazemetostat is a methyltransferase inhibitor indicated to treat patients 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection. 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 Tegaserod interact?

•Drug A: Adalimumab •Drug B: Tegaserod •Severity: MODERATE •Description: The metabolism of Tegaserod 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): Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of adult women less than 65 years of age with irritable bowel syndrome with constipation (IBS-C). The safety and effectiveness of tegaserod in men with IBS-C have not been established. •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 general, it has been determined that tegaserod is an agonist of serotonin type-4 (5-HT(4)) receptors, an antagonist at 5-HT(2B) receptors, but is expected to possess minimal binding to 5-HT(1) receptors, and virtually no affinity for 5-HT(3) or dopamine receptors. In clinical trials with tegaserod, centrally analyzed ECGs were recorded in 4,605 male and female patients receiving tegaserod 6 mg twice daily or placebo for IBS-C and other related motility disorders. No subject receiving the agent had an absolute QTcF above 480 ms. An increase in QTcF of 30 to 60 ms was observed in 7% of patients receiving tegaserod and 8% receiving placebo. An increase in QTcF of greater than 60 ms was observed in 0.3% and 0.2% of subjects, respectively. The effects of tegaserod on the QTcF interval were ultimately not considered to be clinically meaningful. Furthermore, it was determined that there is a potential for tegaserod and its main metabolite (the M29 metabolite) to increase platelet aggregation in vitro. In one in vitro study, at concentrations up to 10-times the maximum plasma concentration (Cmax) at the recommended dose, tegaserod significantly increased platelet aggregation in a concentration-dependent manner up to 74% (range 11% to 74%) compared to a control vehicle (with potentiation by various agonists). In another in vitro study, the M29 metabolite, at concentrations up to 0.6-times the Cmax of M29 also showed a 5% to 16% increase in platelet aggregation compared to the control vehicle. The clinical implications of these in vitro platelet aggregation results remain unclear. •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): Irritable bowel syndrome (IBS) is a complex functional disorder comprised of various abnormal and discomforting effects on the gastrointestinal tract and bowel function. Although the cause of IBS has yet to be formally elucidated, patient experience has demonstrated that the disorder is typically associated with abdominal pain, abdominal distension, cramping or bloating, variations in urgency for bowel movements, feelings of incomplete evacuation, gastroesophageal reflux, and various other effects. In particular, IBS that features constipation as a predominant effect is categorized as constipation-predominant IBS, or IBS-C. Concurrently, 5-Hydroxytryptamine (5-HT, or serotonin) has demonstrated the ability to elicit significant regulatory actions on gastrointestinal motility. Specifically, it has been shown that the activation of 5-HT(4) receptors located on motor neurons and interneurons in the gastrointestinal wall can cause the release of acetylcholine, substance P, and calcitonin gene-related peptide that can all facilitate the propulsion of material through the gut. Moreover, when 5-HT(4) receptors located in smooth muscle cells are also activated, activities that may alleviate symptoms of IBS-C like esophageal relaxation and the inhibition of human colonic circular muscle contraction can also occur. Additionally, activating 5-HT(4) on enteric neurons and enterocytes also cause natural fluid secretion in the gut - an action which also strongly assists in promoting the movement of content along the gastrointestinal tract. Alternatively, it has also been observed that 5-HT may participate in generating visceral hyperalgesia in IBS, an observation supported in part by the finding of increased amounts of 5-HT and its metabolites in the plasma of patients experiencing IBS It has therefore also been proposed that antagonism of 5-HT(2B) receptors can lead to inhibition of both 5-HT mediated gastrointestinal motility and visceral hypersensitivity. Subsequently, because tegaserod is considered to be an agonist of the 5-HT(4) receptor and an antagonist of the 5-HT(2B) receptor at clinically relevant levels, it is believed that tegaserod may elicit its mechanism of action by facilitating activities associated with the activation and antagonism of the 5-HT(4) and 5-HT(2B) receptors, like stimulating peristaltic gastrointestinal reflexes and intestinal secretion, inhibiting visceral sensitivity, enhancing basal motor activity, and normalizing impaired motility throughout the gastrointestinal tract, among other actions. •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 tegaserod is approximately 10% when administered to fasting subjects. The median time of peak tegaserod plasma concentration (Tmax) is approximately one hour (range 0.7 to 2 hours). Nevertheless, when tegaserod was given to individuals thirty minutes before a meal of high-fat and high-calorie content (about 150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat), the AUC was reduced by 40% to 65%, the Cmax was reduced by approximately 20% to 40%, and the median Tmax was 0.7 hours. Additionally, plasma concentrations were similar when tegaserod was administered within thirty minutes before a meal or even two and a half hours after a meal. •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): Although tegaserod is not approved for intravenous administration, data regarding the mean volume of distribution of tegaserod at steady-state is recorded as 368 ± 223 L following research of tegaserod administered intravenously. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding recorded for tegaserod is about 98%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tegaserod is ultimately metabolized by way of hydrolysis and direct glucuronidation. The substance is firstly hydrolyzed in the stomach. It then undergoes oxidization and then conjugation to produce the main circulating tegaserod metabolite in human plasma, the so-called M29 metabolite, or 5-methoxyindole-3-carboxylic acid. Nevertheless, it has been determined that this main circulating metabolite has negligible affinity for 5-HT(4) receptors in vitro. Furthermore, tegaserod can also experience direct N-glucuronidation at each of its three guanidine nitrogens which leads to the generation of three isomeric N-glucuronides - the so-called M43.2, M43.8, and M45.3 metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately two-thirds of an orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine 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 mean terminal elimination half-life documented for tegaserod ranges from 4.6 to 8.1 hours following oral 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): Although tegaserod is not approved for intravenous administration, data regarding the mean plasma clearance of tegaserod is documented as 77 ± 15 L/h following research of tegaserod administered intravenously. •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): Single oral doses of 120 mg (which is 20 times the recommended dose) of tegaserod were administered to three healthy subjects in one study. All three subjects developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain and one developed orthostatic hypotension. In 28 healthy subjects exposed to 90 to 180 mg per day of tegaserod (which is 7.5 to 15 times the recommended daily dosage) for several days, adverse reactions were diarrhea (100%), headache (57%), abdominal pain (18%), flatulence (18%), nausea (7%), and vomiting (7%). Although available data from case reports with tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, animal studies involving maternal dietary administration of tegaserod with doses 45 to 71 times the recommended dose demonstrated decreased body weight, delays in developmental landmarks, and decreased survival in rat pups. Caution and careful consideration of risks versus benefits are recommended before administering tegaserod to a pregnant woman. Despite there being little if any data available regarding the presence of tegaserod in human milk, the effects on the breastfed infant, or the effects on milk production, tegaserod and its metabolites are present in rat milk and the milk to plasma concentration ratio is very high in rats. Subsequently, because of the potential for serious reactions in the breastfed infant, including tumorigenicity, breastfeeding is not recommended during treatment with tegaserod. The safety and effectiveness of tegaserod in pediatric patients has not yet been established. Tegaserod is not indicated in patients that are aged 65 years or older. Tegaserod was not carcinogenic in rats given oral dietary doses up to 180 mg/kg/day (approximately 93 to 111 times the recommended dose based on AUC) for 110 to 124 weeks. In mice, dietary administration of tegaserod for 104 weeks produced mucosal hyperplasia and adenocarcinoma of the small intestine at 600 mg/kg/day (approximately 83 to 110 times the recommended dose based on AUC). There was no evidence of carcinogenicity at lower doses (3 to 35 times the recommended dose based on AUC). Tegaserod was not genotoxic in the in vitro Chinese hamster lung fibroblast (CHL/V79) cell chromosomal aberration and forward mutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test. The results of the Ames test for mutagenicity were equivocal. Tegaserod at oral (dietary) doses up to 240 mg/kg/day (approximately 57 times the recommended dose based on AUC) in male rats and 150 mg/kg/day (approximately 42 times the recommended dose based on AUC) in female rats was found to have no effect on fertility and reproductive performance. Inhibition of the hERG (human Ether-a-go-go-Related Gene) channel was evident only in the micromolar concentration range with an IC50 of 13 micromolar (approximately 1300 times the Cmax in humans at the recommended dose). In in vitro studies, tegaserod had no effects on impulse conduction in isolated guinea pig papillary muscle at up to 100 times the Cmax in humans, Langendorff-perfused isolated rabbit heart (QT interval) at up to 1000 times the Cmax in humans, or human atrial myocytes at multiples up to 10 times the Cmax in humans. The major metabolite, M29, had no effect on QT in the Langendorff-perfused isolated rabbit heart at multiples up to 323 times the Cmax in humans. In anesthetized and conscious dogs, tegaserod at doses up to 92 to 134 times the recommended dose based on Cmax did not alter heart rate, QRS interval duration, QTc or other ECG parameters. In chronic toxicology studies in rats and dogs, there were no treatment-related changes in cardiac morphology after tegaserod administration at doses up to 660 times the recommended dose based on AUC. Although tegaserod is expected to bind to 5-HT2B receptors in humans at the recommended dose, there does not appear to be any potential for heart valve injury based on functional evidence of 5-HT2B receptor antagonism. Studies with isolated coronary and mesenteric blood vessels from non-human primates and humans showed no vasoconstrictor effect at concentrations approximately 100 times the human Cmax. Tegaserod exhibited antagonism of 5-HT-mediated vasoconstriction via 5-HT1B receptors. In rat thoracic aortic rings that were pre-constricted with phenylephrine or norepinephrine, tegaserod produced vasorelaxation, with IC50 values 6 and 64 times the Cmax plasma concentrations in humans, respectively. No effects were observed in the basal tone of aortic rings at concentrations up to 1000 times the human Cmax. In studies with an anesthetized rat model for measuring macro- and micro-circulation of the colon, intraduodenal dosing with tegaserod (approximately 7 times the recommended dose based on Cmax) produced no clinically relevant effect on blood pressure, heart rate, or vascular conductance. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zelnorm •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tégasérod Tegaserod Tegaserodum •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): Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of constipation predominant irritable bowel syndrome (IBS-C) specifically in women under the age of 65. There is currently no safety or efficacy data for use of tegaserol in men.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tegaserod interact? Information: •Drug A: Adalimumab •Drug B: Tegaserod •Severity: MODERATE •Description: The metabolism of Tegaserod 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): Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of adult women less than 65 years of age with irritable bowel syndrome with constipation (IBS-C). The safety and effectiveness of tegaserod in men with IBS-C have not been established. •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 general, it has been determined that tegaserod is an agonist of serotonin type-4 (5-HT(4)) receptors, an antagonist at 5-HT(2B) receptors, but is expected to possess minimal binding to 5-HT(1) receptors, and virtually no affinity for 5-HT(3) or dopamine receptors. In clinical trials with tegaserod, centrally analyzed ECGs were recorded in 4,605 male and female patients receiving tegaserod 6 mg twice daily or placebo for IBS-C and other related motility disorders. No subject receiving the agent had an absolute QTcF above 480 ms. An increase in QTcF of 30 to 60 ms was observed in 7% of patients receiving tegaserod and 8% receiving placebo. An increase in QTcF of greater than 60 ms was observed in 0.3% and 0.2% of subjects, respectively. The effects of tegaserod on the QTcF interval were ultimately not considered to be clinically meaningful. Furthermore, it was determined that there is a potential for tegaserod and its main metabolite (the M29 metabolite) to increase platelet aggregation in vitro. In one in vitro study, at concentrations up to 10-times the maximum plasma concentration (Cmax) at the recommended dose, tegaserod significantly increased platelet aggregation in a concentration-dependent manner up to 74% (range 11% to 74%) compared to a control vehicle (with potentiation by various agonists). In another in vitro study, the M29 metabolite, at concentrations up to 0.6-times the Cmax of M29 also showed a 5% to 16% increase in platelet aggregation compared to the control vehicle. The clinical implications of these in vitro platelet aggregation results remain unclear. •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): Irritable bowel syndrome (IBS) is a complex functional disorder comprised of various abnormal and discomforting effects on the gastrointestinal tract and bowel function. Although the cause of IBS has yet to be formally elucidated, patient experience has demonstrated that the disorder is typically associated with abdominal pain, abdominal distension, cramping or bloating, variations in urgency for bowel movements, feelings of incomplete evacuation, gastroesophageal reflux, and various other effects. In particular, IBS that features constipation as a predominant effect is categorized as constipation-predominant IBS, or IBS-C. Concurrently, 5-Hydroxytryptamine (5-HT, or serotonin) has demonstrated the ability to elicit significant regulatory actions on gastrointestinal motility. Specifically, it has been shown that the activation of 5-HT(4) receptors located on motor neurons and interneurons in the gastrointestinal wall can cause the release of acetylcholine, substance P, and calcitonin gene-related peptide that can all facilitate the propulsion of material through the gut. Moreover, when 5-HT(4) receptors located in smooth muscle cells are also activated, activities that may alleviate symptoms of IBS-C like esophageal relaxation and the inhibition of human colonic circular muscle contraction can also occur. Additionally, activating 5-HT(4) on enteric neurons and enterocytes also cause natural fluid secretion in the gut - an action which also strongly assists in promoting the movement of content along the gastrointestinal tract. Alternatively, it has also been observed that 5-HT may participate in generating visceral hyperalgesia in IBS, an observation supported in part by the finding of increased amounts of 5-HT and its metabolites in the plasma of patients experiencing IBS It has therefore also been proposed that antagonism of 5-HT(2B) receptors can lead to inhibition of both 5-HT mediated gastrointestinal motility and visceral hypersensitivity. Subsequently, because tegaserod is considered to be an agonist of the 5-HT(4) receptor and an antagonist of the 5-HT(2B) receptor at clinically relevant levels, it is believed that tegaserod may elicit its mechanism of action by facilitating activities associated with the activation and antagonism of the 5-HT(4) and 5-HT(2B) receptors, like stimulating peristaltic gastrointestinal reflexes and intestinal secretion, inhibiting visceral sensitivity, enhancing basal motor activity, and normalizing impaired motility throughout the gastrointestinal tract, among other actions. •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 tegaserod is approximately 10% when administered to fasting subjects. The median time of peak tegaserod plasma concentration (Tmax) is approximately one hour (range 0.7 to 2 hours). Nevertheless, when tegaserod was given to individuals thirty minutes before a meal of high-fat and high-calorie content (about 150 calories from protein, 250 calories from carbohydrates, and 500 calories from fat), the AUC was reduced by 40% to 65%, the Cmax was reduced by approximately 20% to 40%, and the median Tmax was 0.7 hours. Additionally, plasma concentrations were similar when tegaserod was administered within thirty minutes before a meal or even two and a half hours after a meal. •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): Although tegaserod is not approved for intravenous administration, data regarding the mean volume of distribution of tegaserod at steady-state is recorded as 368 ± 223 L following research of tegaserod administered intravenously. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The protein binding recorded for tegaserod is about 98%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tegaserod is ultimately metabolized by way of hydrolysis and direct glucuronidation. The substance is firstly hydrolyzed in the stomach. It then undergoes oxidization and then conjugation to produce the main circulating tegaserod metabolite in human plasma, the so-called M29 metabolite, or 5-methoxyindole-3-carboxylic acid. Nevertheless, it has been determined that this main circulating metabolite has negligible affinity for 5-HT(4) receptors in vitro. Furthermore, tegaserod can also experience direct N-glucuronidation at each of its three guanidine nitrogens which leads to the generation of three isomeric N-glucuronides - the so-called M43.2, M43.8, and M45.3 metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately two-thirds of an orally administered dose of tegaserod is excreted unchanged in the feces, with the remaining one-third excreted in the urine 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 mean terminal elimination half-life documented for tegaserod ranges from 4.6 to 8.1 hours following oral 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): Although tegaserod is not approved for intravenous administration, data regarding the mean plasma clearance of tegaserod is documented as 77 ± 15 L/h following research of tegaserod administered intravenously. •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): Single oral doses of 120 mg (which is 20 times the recommended dose) of tegaserod were administered to three healthy subjects in one study. All three subjects developed diarrhea and headache. Two of these subjects also reported intermittent abdominal pain and one developed orthostatic hypotension. In 28 healthy subjects exposed to 90 to 180 mg per day of tegaserod (which is 7.5 to 15 times the recommended daily dosage) for several days, adverse reactions were diarrhea (100%), headache (57%), abdominal pain (18%), flatulence (18%), nausea (7%), and vomiting (7%). Although available data from case reports with tegaserod use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, animal studies involving maternal dietary administration of tegaserod with doses 45 to 71 times the recommended dose demonstrated decreased body weight, delays in developmental landmarks, and decreased survival in rat pups. Caution and careful consideration of risks versus benefits are recommended before administering tegaserod to a pregnant woman. Despite there being little if any data available regarding the presence of tegaserod in human milk, the effects on the breastfed infant, or the effects on milk production, tegaserod and its metabolites are present in rat milk and the milk to plasma concentration ratio is very high in rats. Subsequently, because of the potential for serious reactions in the breastfed infant, including tumorigenicity, breastfeeding is not recommended during treatment with tegaserod. The safety and effectiveness of tegaserod in pediatric patients has not yet been established. Tegaserod is not indicated in patients that are aged 65 years or older. Tegaserod was not carcinogenic in rats given oral dietary doses up to 180 mg/kg/day (approximately 93 to 111 times the recommended dose based on AUC) for 110 to 124 weeks. In mice, dietary administration of tegaserod for 104 weeks produced mucosal hyperplasia and adenocarcinoma of the small intestine at 600 mg/kg/day (approximately 83 to 110 times the recommended dose based on AUC). There was no evidence of carcinogenicity at lower doses (3 to 35 times the recommended dose based on AUC). Tegaserod was not genotoxic in the in vitro Chinese hamster lung fibroblast (CHL/V79) cell chromosomal aberration and forward mutation test, the in vitro rat hepatocyte unscheduled DNA synthesis (UDS) test or the in vivo mouse micronucleus test. The results of the Ames test for mutagenicity were equivocal. Tegaserod at oral (dietary) doses up to 240 mg/kg/day (approximately 57 times the recommended dose based on AUC) in male rats and 150 mg/kg/day (approximately 42 times the recommended dose based on AUC) in female rats was found to have no effect on fertility and reproductive performance. Inhibition of the hERG (human Ether-a-go-go-Related Gene) channel was evident only in the micromolar concentration range with an IC50 of 13 micromolar (approximately 1300 times the Cmax in humans at the recommended dose). In in vitro studies, tegaserod had no effects on impulse conduction in isolated guinea pig papillary muscle at up to 100 times the Cmax in humans, Langendorff-perfused isolated rabbit heart (QT interval) at up to 1000 times the Cmax in humans, or human atrial myocytes at multiples up to 10 times the Cmax in humans. The major metabolite, M29, had no effect on QT in the Langendorff-perfused isolated rabbit heart at multiples up to 323 times the Cmax in humans. In anesthetized and conscious dogs, tegaserod at doses up to 92 to 134 times the recommended dose based on Cmax did not alter heart rate, QRS interval duration, QTc or other ECG parameters. In chronic toxicology studies in rats and dogs, there were no treatment-related changes in cardiac morphology after tegaserod administration at doses up to 660 times the recommended dose based on AUC. Although tegaserod is expected to bind to 5-HT2B receptors in humans at the recommended dose, there does not appear to be any potential for heart valve injury based on functional evidence of 5-HT2B receptor antagonism. Studies with isolated coronary and mesenteric blood vessels from non-human primates and humans showed no vasoconstrictor effect at concentrations approximately 100 times the human Cmax. Tegaserod exhibited antagonism of 5-HT-mediated vasoconstriction via 5-HT1B receptors. In rat thoracic aortic rings that were pre-constricted with phenylephrine or norepinephrine, tegaserod produced vasorelaxation, with IC50 values 6 and 64 times the Cmax plasma concentrations in humans, respectively. No effects were observed in the basal tone of aortic rings at concentrations up to 1000 times the human Cmax. In studies with an anesthetized rat model for measuring macro- and micro-circulation of the colon, intraduodenal dosing with tegaserod (approximately 7 times the recommended dose based on Cmax) produced no clinically relevant effect on blood pressure, heart rate, or vascular conductance. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zelnorm •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tégasérod Tegaserod Tegaserodum •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): Tegaserod is a serotonin-4 (5-HT4) receptor agonist indicated for the treatment of constipation predominant irritable bowel syndrome (IBS-C) specifically in women under the age of 65. There is currently no safety or efficacy data for use of tegaserol in men. 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 Telithromycin interact?

•Drug A: Adalimumab •Drug B: Telithromycin •Severity: MODERATE •Description: The metabolism of Telithromycin 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): For the treatment of Pneumococcal infection, acute sinusitis, acute bacterial tonsillitis, acute bronchitis and bronchiolitis, lower respiratory tract infection and lobar (pneumococcal) pneumonia. •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): Telithromycin is a ketolide antibiotic which has an antimicrobial spectrum similar or slightly broader than that of penicillin. It is often used as an alternative in patients who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma. Telithromycin prevents bacterial growth by binding to bacterial 50S ribosomal subunits and interfering with bacterial peptide translocation and elongation. •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): Telithromycin acts by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g. Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the binding site at domain V. Telithromycin may also inhibit the assembly of nascent ribosomal units. Compared to erythromycin A, telithromycin binds to the 23S rRNA with 10 times greater affinity in erythromycin-susceptible organisms and 25 times greater affinity in macrolide-resistant strains. This increased binding affinity may be conferred by the C11-12 carbamate side chain of telithromycin. The side chain appears to maintain binding at domain II in the presence of resistance mediated by alterations in domain V. •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): Absolute bioavailability is approximately 57%. Maximal concentrations are reached 0.5 - 4 hours following oral administration. Food intake does not affected 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): 2.9 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60 - 70% bound primarily to human serum albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic - estimated 50% metabolized by CYP3A4 and 50% metabolized independent of cytochrome P450 •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver. •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): Main elimination half-life is 2-3 hours; terminal elimination half-life is 10 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): LD50>2000 mg/kg (PO in rats). Adverse effects are similar to those of clarithormycin and erithromycin and include diarrhea, nausea, vomiting, loose stools, abdominal pain, flatulence and dyspepsia. It may also cause dizziness, headache and taste disturbances. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ketek •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): Telithromycin is an ketolide used to treat community acquired pneumonia of mild to moderate severity.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Telithromycin interact? Information: •Drug A: Adalimumab •Drug B: Telithromycin •Severity: MODERATE •Description: The metabolism of Telithromycin 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): For the treatment of Pneumococcal infection, acute sinusitis, acute bacterial tonsillitis, acute bronchitis and bronchiolitis, lower respiratory tract infection and lobar (pneumococcal) pneumonia. •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): Telithromycin is a ketolide antibiotic which has an antimicrobial spectrum similar or slightly broader than that of penicillin. It is often used as an alternative in patients who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma. Telithromycin prevents bacterial growth by binding to bacterial 50S ribosomal subunits and interfering with bacterial peptide translocation and elongation. •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): Telithromycin acts by binding to domains II and V of 23S rRNA of the 50S ribosomal subunit. By binding at domain II, telithromycin retains activity against gram-positive cocci (e.g. Streptococcus pneumoniae) in the presence of resistance mediated by methylases (erm genes) that alter the binding site at domain V. Telithromycin may also inhibit the assembly of nascent ribosomal units. Compared to erythromycin A, telithromycin binds to the 23S rRNA with 10 times greater affinity in erythromycin-susceptible organisms and 25 times greater affinity in macrolide-resistant strains. This increased binding affinity may be conferred by the C11-12 carbamate side chain of telithromycin. The side chain appears to maintain binding at domain II in the presence of resistance mediated by alterations in domain V. •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): Absolute bioavailability is approximately 57%. Maximal concentrations are reached 0.5 - 4 hours following oral administration. Food intake does not affected 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): 2.9 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 60 - 70% bound primarily to human serum albumin •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic - estimated 50% metabolized by CYP3A4 and 50% metabolized independent of cytochrome P450 •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The systemically available telithromycin is eliminated by multiple pathways as follows: 7% of the dose is excreted unchanged in feces by biliary and/or intestinal secretion; 13% of the dose is excreted unchanged in urine by renal excretion; and 37% of the dose is metabolized by the liver. •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): Main elimination half-life is 2-3 hours; terminal elimination half-life is 10 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): LD50>2000 mg/kg (PO in rats). Adverse effects are similar to those of clarithormycin and erithromycin and include diarrhea, nausea, vomiting, loose stools, abdominal pain, flatulence and dyspepsia. It may also cause dizziness, headache and taste disturbances. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ketek •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): Telithromycin is an ketolide used to treat community acquired pneumonia of mild to moderate severity. 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 Temozolomide interact?

•Drug A: Adalimumab •Drug B: Temozolomide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Temozolomide. •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): Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma. •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): Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10 /L and a platelet count of ≥100 x 10 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, 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): Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future. •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): Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T max of one hour. Following a single oral dose of 150 mg/m, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m /day. The median T max is 1 hour Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 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): Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide. •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): Temozolomide has a mean elimination half-life of 1.8 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): Temozolomide has a clearance of approximately 5.5 L/hr/m. •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 primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Temodar, Temomedac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-perillyl alcohol temozolomide Methazolastone Temozolodida Temozolomid Temozolomida Témozolomide Temozolomide Temozolomidum TMZ •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): Temozolomide is an alkylating agent used to treat glioblastoma multiforme and refractory anaplastic astrocytoma.

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 Temozolomide interact? Information: •Drug A: Adalimumab •Drug B: Temozolomide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Temozolomide. •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): Temozolomide is indicated in adult patients for the treatment of newly diagnosed glioblastoma concomitantly with radiotherapy and for use as maintenance treatment thereafter. It is also indicated for the treatment of refractory anaplastic astrocytoma in adult patients or adjuvant therapy for adults with newly diagnosed anaplastic astrocytoma. •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): Temozolomide is a prodrug of the imidazotetrazine class that requires nonenzymatic hydrolysis at physiological pH in vivo to perform alkylation of adenine/guanine residues, leading to DNA damage through futile repair cycles and eventual cell death. Temozolomide treatment is associated with myelosuppression, which is likely to be more severe in females and geriatric patients. Patients must have an ANC of ≥1.5 x 10 /L and a platelet count of ≥100 x 10 /L before starting therapy and must be monitored weekly during the concomitant radiotherapy phase, on days one and 22 of maintenance cycles, and weekly at any point where the ANC/platelet count falls below the specified values until recovery. Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have been observed following temozolomide administration. Pneumocystis pneumonia may occur in patients undergoing treatment, and prophylaxis should be provided for patients in the concomitant phase of therapy with monitoring at all stages. Severe hepatotoxicity has also been reported, and liver testing should be performed at baseline, midway through the first cycle, before each subsequent cycle, and approximately two to four weeks after the last dose. Animal studies suggest that temozolomide has significant embryo-fetal toxicity; male and female patients should practice contraception up to three and six months following the last dose of temozolomide, 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): Glioblastoma (glioblastoma multiforme) is the most common and aggressive adult primary brain tumour, accounting for 45.6% of all primary malignant brain tumours. Primarily defined histopathologically by necrosis and microvascular proliferation (WHO grade IV classification), glioblastomas are commonly treated through radiotherapy and concomitant alkylation-based chemotherapy with temozolomide. Temozolomide (TMZ) is a small (194 Da) lipophilic alkylating agent of the imidazotetrazine class that is stable at acidic pH, allowing for both oral and intravenous dosing, and can cross the blood-brain barrier to affect CNS tumours. After absorption, TMZ undergoes spontaneous nonenzymatic breakdown at physiological pH to form 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC), which then reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation. Brain tumours such as glioblastoma typically possess a more alkaline pH than healthy tissue, favouring TMZ activation within tumour tissue. The methyl diazonium cation is highly reactive and methylates DNA at the N7 position of guanine (N7-MeG, 70%), the N3 position of adenine (N3-MeA, 9%), and the O6 position of guanine (O6-MeG, 6%). Although more prevalent, N7-MeG and N3-MeA are rapidly repaired by the base excision repair pathway and are not primary mediators of temozolomide toxicity, although N3-MeA lesions are lethal if not repaired. By comparison, repair of O6-MeG requires action by the suicide enzyme methylguanine-DNA methyltransferase (MGMT), which removes the methyl group to restore guanine. If not repaired by MGMT, O6-MeG mispairs with thymine, activating the DNA mismatch repair (MMR) pathway that removes the thymine (not the O6-MeG), resulting in futile cycles of repair and eventual DNA strand breaks leading to apoptosis. As MMR activity is crucial for temozolomide cytotoxicity, cells that have reduced or absent MGMT function and an intact MMR pathway are the most sensitive to temozolomide treatment. Glioblastomas that upregulate MGMT downregulate MMR or alter both are resistant to TMZ, leading to treatment failure. More recently, increased interest has also been shown in the immunomodulatory effects of TMZ, related to its myelosuppressive effects. Counterintuitively, lymphodepletion may enhance the antitumour effects of cellular immunotherapy and improve the dynamics of memory cells by altering tumour-specific versus tumour-tolerant populations. The depletion of tumour-localized immunosuppressive T reg cells may contribute to an improved response to immunotherapy. Hence, TMZ treatment may also form the backbone of immunotherapy strategies against glioblastoma in the future. •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): Temozolomide is rapidly and completely absorbed in the gastrointestinal tract and is stable at both acidic and neutral pH. Therefore, temozolomide may be administered both orally and intravenously with a median T max of one hour. Following a single oral dose of 150 mg/m, temozolomide and its active MTIC metabolite had C max values of 7.5 μg/mL and 282 ng/mL and AUC values of 23.4 μg*hr/mL and 864 ng*hr/mL, respectively. Similarly, following a single 90-minute IV infusion of 150 mg/m, temozolide and its active MTIC metabolite had C max values of 7.3 μg/mL and 276 ng/mL and AUC values of 24.6 μg*hr/mL and 891 ng*hr/mL, respectively. Temozolomide kinetics are linear over the range of 75-250 mg/m /day. The median T max is 1 hour Oral temozolomide absorption is affected by food. Administration following a high-fat breakfast of 587 calories caused the mean C max and AUC to decrease by 32% and 9%, respectively, and the median T max to increase by 2-fold (from 1-2.25 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): Temozolomide has a mean apparent volume of distribution (%CV) of 0.4 (13%) L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Temozolomide plasma protein binding varies from 8-36%, with an average of around 15%. In vitro binding experiments revealed approximate dissociation constants of 0.2-0.25 and 0.12 mM for temozolomide with human serum albumin (HSA) and alpha-1-acid glycoprotein (AGP), respectively; despite the slightly higher affinity for AGP, it is likely that temozolomide is predominantly bound to HSA due to its higher serum concentration. In addition, temozolomide binding to HSA results in delayed hydrolysis and a longer half-life than in buffer (1 versus 1.8 hours). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): After absorption, temozolomide undergoes nonenzymatic chemical conversion to the active metabolite 5-(3-methyltriazen-1-yl) imidazole-4-carboxamide (MTIC) plus carbon dioxide and to a temozolomide acid metabolite, which occurs at physiological pH but is enhanced with increasing alkalinity. MTIC subsequently reacts with water to produce 5-aminoimidazole-4-carboxamide (AIC) and a highly reactive methyl diazonium cation, the active alkylating species. The cytochrome P450 system plays only a minor role in temozolomide metabolism. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Roughly 38% of administered temozolomide can be recovered over seven days, with 38% in the urine and only 0.8% in the feces. The recovered material comprises mainly metabolites: unidentified polar metabolites (17%), AIC (12%), and the temozolomide acid metabolite (2.3%). Only 6% of the recovered dose represents unchanged temozolomide. •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): Temozolomide has a mean elimination half-life of 1.8 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): Temozolomide has a clearance of approximately 5.5 L/hr/m. •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 primary dose-limiting toxicity of temozolomide is myelosuppression, which can occur with any dose but is more severe at higher doses. Patients taking high doses experienced adverse reactions, including severe and prolonged myelosuppression, infections, and death. One patient who took 2000 mg/day for five days experienced pancytopenia, pyrexia, and multi-organ failure, which resulted in death. Patients experiencing an overdose should have complete blood counts monitored and provided with supportive care as necessary. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Temodar, Temomedac •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): (S)-perillyl alcohol temozolomide Methazolastone Temozolodida Temozolomid Temozolomida Témozolomide Temozolomide Temozolomidum TMZ •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): Temozolomide is an alkylating agent used to treat glioblastoma multiforme and refractory anaplastic astrocytoma. 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 Temsirolimus interact?

•Drug A: Adalimumab •Drug B: Temsirolimus •Severity: MAJOR •Description: The metabolism of Temsirolimus 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 renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma. •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): Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor. •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): Infused intravenous over 30 - 60 minutes. C max is typically observed at the end of infusion •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 in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 87% bound to plasma proteins in vitro at a concentration of 100 ng/ml •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection. •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): Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, 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): 16.2 L/h (22%) •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): Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Torisel •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): Temsirolimus is a antineoplastic agent used in the treatment of renal cell carcinoma (RCC) that works by inhibiting mTOR.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Temsirolimus interact? Information: •Drug A: Adalimumab •Drug B: Temsirolimus •Severity: MAJOR •Description: The metabolism of Temsirolimus 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 renal cell carcinoma (RCC). Also investigated for use/treatment in breast cancer, lymphoma (unspecified), rheumatoid arthritis, and multiple myeloma. •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): Temsirolimus is an inhibitor of mTOR (mammalian target of rapamycin). Temsirolimus binds to an intracellular protein (FKBP-12), and the protein-drug complex inhibits the activity of mTOR that controls cell division. Inhibition of mTOR activity resulted in a G1 growth arrest in treated tumor cells. When mTOR was inhibited, its ability to phosphorylate p70S6k and S6 ribosomal protein, which are downstream of mTOR in the PI3 kinase/AKT pathway was blocked. In in vitro studies using renal cell carcinoma cell lines, temsirolimus inhibited the activity of mTOR and resulted in reduced levels of the hypoxia-inducible factors HIF-1 and HIF-2 alpha, and the vascular endothelial growth factor. •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): Infused intravenous over 30 - 60 minutes. C max is typically observed at the end of infusion •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 in whole blood of cancer patients; both temsirolimus and sirolimus are extensive distributed partitioned into formed blood elements •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 87% bound to plasma proteins in vitro at a concentration of 100 ng/ml •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Primarily metabolized by cytochrome P450 3A4 in the human liver. Sirolimus, an equally potent metabolite, is the primary metabolite in humans following IV infusion. Other metabolic pathways observed in in vitro temsirolimus metabolism studies include hydroxylation, reduction and demethylation. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Excreted predominantly in feces (76%), 4.6% of drug and metabolites recovered in urine. 17% of drug was not recovered by either route following a 14-day sample collection. •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): Temsirolimus exhibits a bi-exponential decline in whole blood concentrations and the mean half-lives of temsirolimus and sirolimus were 17.3 hr and 54.6 hr, 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): 16.2 L/h (22%) •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): Temsirolimus has been administered to patients with cancer in phase 1 and 2 trials with repeated intravenous doses as high as 220 mg/m2. The risk of several serious adverse events, including thrombosis, bowel perforation, interstitial lung disease (ILD), seizure, and psychosis, is increased with doses of temsirolimus greater than 25 mg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Torisel •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): Temsirolimus is a antineoplastic agent used in the treatment of renal cell carcinoma (RCC) that works by inhibiting mTOR. 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 Teniposide interact?

•Drug A: Adalimumab •Drug B: Teniposide •Severity: MAJOR •Description: The metabolism of Teniposide 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 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): Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia •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): Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. •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 appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. •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): From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the 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): 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): 10.3 mL/min/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): 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): Epidophyllotoxin Teniposid Téniposide Teniposide Teniposido Teniposidum •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): Teniposide is a cytotoxic drug used as an adjunct for chemotherapy induction in the treatment of refractory childhood acute lymphoblastic 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 CYP2C19 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Teniposide interact? Information: •Drug A: Adalimumab •Drug B: Teniposide •Severity: MAJOR •Description: The metabolism of Teniposide 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 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): Teniposide is used for the treatment of refractory acute lymphoblastic leukaemia •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): Teniposide is a phase-specific cytotoxic drug, acting in the late S or early G 2 phase of the cell cycle. Teniposide prevents cell mitosis by causing single and double stranded DNA breaks as well as cross linking between protein and DNA. •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 appears to be related to the inhibition of type II topoisomerase activity since teniposide does not intercalate into DNA or bind strongly to DNA. Teniposide binds to and inhibits DNA topoisomerase II. The cytotoxic effects of teniposide are related to the relative number of double-stranded DNA breaks produced in cells, which are a reflection of the stabilization of a topoisomerase II-DNA intermediate. •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): From 4% to 12% of a dose is excreted in urine as parent drug. Fecal excretion of radioactivity within 72 hours after dosing accounted for 0% to 10% of the 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): 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): 10.3 mL/min/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): 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): Epidophyllotoxin Teniposid Téniposide Teniposide Teniposido Teniposidum •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): Teniposide is a cytotoxic drug used as an adjunct for chemotherapy induction in the treatment of refractory childhood acute lymphoblastic 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 CYP2C19 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Tenofovir alafenamide interact?

•Drug A: Adalimumab •Drug B: Tenofovir alafenamide •Severity: MODERATE •Description: The metabolism of Tenofovir alafenamide 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): Tenofovir alafenamide is indicated for the treatment of hepatitis B virus infection in adults and pediatric patients 12 years of age and older with compensated liver disease. In combination with emtricitabine and other antiretrovirals, it is indicated for the treatment of HIV-1 infection in adolescent and adult patients with a weight higher than 35 kg. This combination is also indicated to prevent HIV-1 infections in high risk adolescent and adult patients, excluding patients at risk from receptive vaginal sex. When combined with antiretrovirals other than protease inhibitors that require a CYP3A inhibitor, it can be used to treat pediatric patients weighing 25-35 kg. In the combination product with emtricitabine and bictegravir, tenofovir alafenamide is considered a complete treatment regimen for HIV-1 infections for treatment-naive patients or patients virologically suppressed for at least three months with no history of treatment failure. Additionally, the combination product including elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide and the combination product including emtricitabine, rilpivirine and tenofovir alafenamide can be used in the treatment of HIV-1 infection in patients older than 12 years with no previous antiretroviral therapy history or who are virologically suppressed for at least 6 months with no history of treatment failure. The combination product including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for the treatment of HIV-1 infection in adults without prior antiretroviral therapy or in patients virologically suppressed for 6 months and no reported resistance to darunavir or tenofovir. •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): Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication. Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart tenofovir disoproxil. This improved safety profile seems to be related to a lower plasma concentration of tenofovir. In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil. •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): Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil. This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate. Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells. Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis. To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir. •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): As compared to the parent molecule, tenofovir, tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability. Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation. Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal 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): In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tenofovir alafenamide is reported to bind to plasma proteins and ex vivo studies have registered that approximately 80% of the administered dose of this drug is presented in a bound state. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound tenofovir by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells. After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged tenofovir followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir. •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 for tenofovir alafenamide is of 0.51 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 clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 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): The LD 50 of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%. Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Biktarvy, Descovy, Genvoya, Odefsey, Vemlidy •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): Tenofovir alafenamide is a nucleoside analog reverse transcriptase inhibitor used for the treatment of chronic hepatitis B virus infection in adults with compensated liver 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 CYP3A4 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Tenofovir alafenamide interact? Information: •Drug A: Adalimumab •Drug B: Tenofovir alafenamide •Severity: MODERATE •Description: The metabolism of Tenofovir alafenamide 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): Tenofovir alafenamide is indicated for the treatment of hepatitis B virus infection in adults and pediatric patients 12 years of age and older with compensated liver disease. In combination with emtricitabine and other antiretrovirals, it is indicated for the treatment of HIV-1 infection in adolescent and adult patients with a weight higher than 35 kg. This combination is also indicated to prevent HIV-1 infections in high risk adolescent and adult patients, excluding patients at risk from receptive vaginal sex. When combined with antiretrovirals other than protease inhibitors that require a CYP3A inhibitor, it can be used to treat pediatric patients weighing 25-35 kg. In the combination product with emtricitabine and bictegravir, tenofovir alafenamide is considered a complete treatment regimen for HIV-1 infections for treatment-naive patients or patients virologically suppressed for at least three months with no history of treatment failure. Additionally, the combination product including elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide and the combination product including emtricitabine, rilpivirine and tenofovir alafenamide can be used in the treatment of HIV-1 infection in patients older than 12 years with no previous antiretroviral therapy history or who are virologically suppressed for at least 6 months with no history of treatment failure. The combination product including darunavir, cobicistat, emtricitabine, and tenofovir alafenamide is indicated for the treatment of HIV-1 infection in adults without prior antiretroviral therapy or in patients virologically suppressed for 6 months and no reported resistance to darunavir or tenofovir. •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): Tenofovir alafenamide has been shown to be a potent inhibitor of hepatitis B viral replication. Tenofovir alafenamide presents a better renal tolerance when compared with the counterpart tenofovir disoproxil. This improved safety profile seems to be related to a lower plasma concentration of tenofovir. In clinical trials, tenofovir alafenamide was shown to present 5-fold more potent antiviral activity against HIV-1 when compared to tenofovir disoproxil. •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): Tenofovir alafenamide presents 91% lower plasma concentration with an intracellular presence of about 20-fold higher when compared to tenofovir disoproxil. This is due to its prolonged systemic exposure and its higher intracellular accumulation of the active metabolite tenofovir diphosphate. Tenofovir alafenamide accumulates more in peripheral blood mononuclear cells compared to red blood cells. Once activated, tenofovir acts with different mechanisms including the inhibition of viral polymerase, causing chain termination and the inhibition of viral synthesis. To know more about the specific mechanism of action of the active form, please visit the drug entry of tenofovir. •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): As compared to the parent molecule, tenofovir, tenofovir alafenamide presents a lipophilic group that masks the negative charge of the parent moiety which improves its oral bioavailability. Tenofovir alafenamide is highly stable in plasma and, after administration of this prodrug, there is a low concentration of tenofovir in plasma. After oral administration, tenofovir alafenamide is rapidly absorbed by the gut. When a single dose is administered, a peak concentration of 16 ng/ml of the parent compound, corresponding to about 73% of the dose, is observed after 2 hours with an AUC of 270 ng*h/mL. Once inside the body, tenofovir alafenamide enters hepatocytes by passive diffusion regulated by the organic anion transporters 1B1 and 1B3 for its activation. Administration of tenofovir alafenamide concomitantly with a high-fat meal results in an increase of about 65% in its internal 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): In clinical trials, the reported volume of distribution of tenofovir alafenamide was higher than 100 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tenofovir alafenamide is reported to bind to plasma proteins and ex vivo studies have registered that approximately 80% of the administered dose of this drug is presented in a bound state. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): To be activated, tenofovir alafenamide is required to be hydrolyzed to the parent compound tenofovir by the activity of cathepsin A or carboxylesterase 1. Tenofovir alafenamide presents significant plasma stability and hence, its activation is performed inside the target cells. After activation, tenofovir is further processed and after 1-2 days, it is detected in plasma almost completely transformed to uric acid. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tenofovir alafenamide has been registered to present a bile elimination that corresponds to 47% of the administered dose and a renal elimination the represents about 36%. From the recovered dose in urine, about 75% is represented as unchanged tenofovir followed by uric acid and a small dose of tenofovir alafenamide. On the other hand, in feces, 99% of the recovered dose corresponds to tenofovir. •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 for tenofovir alafenamide is of 0.51 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 clearance rate of tenofovir alafenamide is 117 L/h. In patients with severe renal impairment, this value can be decreased by 50%, reporting a rate of 61.7 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): The LD 50 of tenofovir alafenamide has not been reported. In cases of overdose, continuous monitoring of vital signs is required as the adverse effects in high doses has not been evaluated. However, in case of overdose, tenofovir is efficiently removed by hemodialysis with an extraction coefficient of 54%. Carcinogenic reports have only been performed with tenofovir disoproxil and it is important to consider that tenofovir alafenamide does not present a high systemic exposure. However, long-term exposure with 10-fold dosages of tenofovir disoproxil was reported to produce liver adenomas in females. Tenofovir alafenamide was not reported to present mutagenic potential and it did not present effects on fertility. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Biktarvy, Descovy, Genvoya, Odefsey, Vemlidy •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): Tenofovir alafenamide is a nucleoside analog reverse transcriptase inhibitor used for the treatment of chronic hepatitis B virus infection in adults with compensated liver 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 CYP3A4 substrates. The severity of the interaction is moderate.

Does Adalimumab and Tenoxicam interact?

•Drug A: Adalimumab •Drug B: Tenoxicam •Severity: MODERATE •Description: The metabolism of Tenoxicam 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 of rheumatoid arthritis, osteoarthritis, backache, and 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): Tenoxicam, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute 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): The antiinflammatory effects of tenoxicam may result from the inhibition of the enzyme cycooxygenase and the subsequent peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, their inhibition accounts for the peripheral analgesic effects of tenoxicam. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •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 absorption of tenoxicam is rapid and complete (absolute bioavailability 100%). •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): Tenoxicam is metabolized in the liver to several pharmacologically inactive metabolites (mainly 5'-hydroxy-tenoxicam). •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): 72 hours (range 59 to 74 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): Tenoxicam is an anti inflammatory analgesic used to treat mild to moderate pain as well as the signs and symptoms of rheumatoid arthritis and osteoarthritis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tenoxicam interact? Information: •Drug A: Adalimumab •Drug B: Tenoxicam •Severity: MODERATE •Description: The metabolism of Tenoxicam 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 of rheumatoid arthritis, osteoarthritis, backache, and 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): Tenoxicam, an antiinflammatory agent with analgesic and antipyretic properties, is used to treat osteoarthritis and control acute 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): The antiinflammatory effects of tenoxicam may result from the inhibition of the enzyme cycooxygenase and the subsequent peripheral inhibition of prostaglandin synthesis. As prostaglandins sensitize pain receptors, their inhibition accounts for the peripheral analgesic effects of tenoxicam. Antipyresis may occur by central action on the hypothalamus, resulting in peripheral dilation, increased cutaneous blood flow, and subsequent heat loss. •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 absorption of tenoxicam is rapid and complete (absolute bioavailability 100%). •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): Tenoxicam is metabolized in the liver to several pharmacologically inactive metabolites (mainly 5'-hydroxy-tenoxicam). •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): 72 hours (range 59 to 74 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): Tenoxicam is an anti inflammatory analgesic used to treat mild to moderate pain as well as the signs and symptoms of rheumatoid arthritis and osteoarthritis. 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 Teplizumab interact?

•Drug A: Adalimumab •Drug B: Teplizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Teplizumab. •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): Teplizumab is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D. •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): Teplizumab is a monoclonal antibody that binds to CD3 molecules on the surface of CD4+ and CD8+ T cells, both involved in the destruction of pancreatic β cells. Several studies have detected an increase in C-peptide levels in early-onset type 1 diabetes (T1D) patients treated with teplizumab, suggesting an improved β cell function. The exposure-response relationship and the safety and effectiveness pharmacodynamic time-response of teplizumab have not been fully elucidated. In the absence of T cell depletion, the use of teplizumab in a 14-day course of treatment can lead to the development of lymphopenia. Cytokine release syndrome (CRS) has also been detected in patients treated with teplizumab. The main manifestations of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these manifestations occurred in the first 5 days of treatment. In addition, the use of teplizumab may lead to the development of serious infections and hypersensitivity reactions. •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): Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms. The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition. Combined with other observations from animal and human studies, it is clear that T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions. The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response. Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 and inhibits T cell activation through steric inhibition of antigen recognition. Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D. However, the exact mechanism underlying this effect remains clear. One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further β cell destruction. Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8 central memory (CD8CM) T cells. It is clear, however, that treatment is most effective in patients who have not yet progressed to Stage 3 and who have an active immune response. •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): During the 14-day treatment course of teplizumab, steady-state concentrations are not expected to be achieved. •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 60 kg subject, teplizumab has a central volume of distribution (Vd) of 2.27 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): As a monoclonal antibody, teplizumab is expected to be metabolized into small peptides by proteases throughout the body. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Teplizumab showed saturable binding and 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): In a 60 kg subject, teplizumab has a mean terminal elimination half-life of 4.5 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): In a 60 kg subject, teplizumab has a clearance of 2.7 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): Toxicity information regarding teplizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious infections, lymphopenia and cytokine release syndrome. Symptomatic and supportive measures are recommended. The mutagenic and carcinogenic potential of teplizumab has not been evaluated. As an antibody, teplizumab is not expected to interact directly with DNA. In female and male mice, teplizumab did not have significant effects in fertility and reproductive performance when administered subcutaneously at doses up to 20 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tzield •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): Teplizumab is a CD3-directed monoclonal antibody indicated to delay the onset of Stage 3 type 1 diabetes in patients with Stage 2 type 1 diabetes.

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 Teplizumab interact? Information: •Drug A: Adalimumab •Drug B: Teplizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Teplizumab. •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): Teplizumab is indicated to delay the onset of Stage 3 type 1 diabetes (T1D) in adults and pediatric patients aged 8 years and older with Stage 2 T1D. •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): Teplizumab is a monoclonal antibody that binds to CD3 molecules on the surface of CD4+ and CD8+ T cells, both involved in the destruction of pancreatic β cells. Several studies have detected an increase in C-peptide levels in early-onset type 1 diabetes (T1D) patients treated with teplizumab, suggesting an improved β cell function. The exposure-response relationship and the safety and effectiveness pharmacodynamic time-response of teplizumab have not been fully elucidated. In the absence of T cell depletion, the use of teplizumab in a 14-day course of treatment can lead to the development of lymphopenia. Cytokine release syndrome (CRS) has also been detected in patients treated with teplizumab. The main manifestations of CRS include fever, nausea, fatigue, headache, myalgia, arthralgia, increased alanine aminotransferase, increased aspartate aminotransferase, and increased total bilirubin; these manifestations occurred in the first 5 days of treatment. In addition, the use of teplizumab may lead to the development of serious infections and hypersensitivity reactions. •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): Type 1 diabetes (T1D) is an autoimmune condition in which T cell-mediated destruction of pancreatic β cells leads to loss of insulin production, impaired glycemic control, and reliance on exogenous insulin. T1D is a progressive disease with three recognizable stages and in which only Stage 3 is associated with clinically apparent symptoms. The earliest indication of T1D risk is the presence of at least two autoantibodies against relevant antigens, confirming an important role for B cells in what has traditionally been considered a T cell-dominated condition. Combined with other observations from animal and human studies, it is clear that T and B cells play a role in T1D; treatment has focussed on targeting each of them independently, as well as their interactions. The T cell receptor (TCR) comprises TCR α and β chains together with six CD3 molecules, including two CD3 ε chains. It is responsible for recognizing antigens displayed on the MHC complex of other cells to elicit a response. Teplizumab, a humanized IgG1κ Fc-nonbinding version of an existing mouse OKT3 antibody (also designated huOKT3γala-ala), is specific for the ε chain of CD3 and inhibits T cell activation through steric inhibition of antigen recognition. Recently, teplizumab has shown efficacy in delaying the time to diagnosis in patients at high risk of developing T1D. However, the exact mechanism underlying this effect remains clear. One hypothesis is that teplizumab acts as a partial agonist at the TCR, increasing the number of exhausted T cells positive for KLRG1, TIGIT, and CD8. These exhausted T cells persist but cannot perform effector functions and, therefore, would be unlikely to contribute to further β cell destruction. Other studies have noted changes in the T cell populations of clinical responders, including an increase in circulating CD8 central memory (CD8CM) T cells. It is clear, however, that treatment is most effective in patients who have not yet progressed to Stage 3 and who have an active immune response. •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): During the 14-day treatment course of teplizumab, steady-state concentrations are not expected to be achieved. •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 60 kg subject, teplizumab has a central volume of distribution (Vd) of 2.27 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): As a monoclonal antibody, teplizumab is expected to be metabolized into small peptides by proteases throughout the body. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Teplizumab showed saturable binding and 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): In a 60 kg subject, teplizumab has a mean terminal elimination half-life of 4.5 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): In a 60 kg subject, teplizumab has a clearance of 2.7 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): Toxicity information regarding teplizumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as serious infections, lymphopenia and cytokine release syndrome. Symptomatic and supportive measures are recommended. The mutagenic and carcinogenic potential of teplizumab has not been evaluated. As an antibody, teplizumab is not expected to interact directly with DNA. In female and male mice, teplizumab did not have significant effects in fertility and reproductive performance when administered subcutaneously at doses up to 20 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tzield •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): Teplizumab is a CD3-directed monoclonal antibody indicated to delay the onset of Stage 3 type 1 diabetes in patients with Stage 2 type 1 diabetes. 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 Teprotumumab interact?

•Drug A: Adalimumab •Drug B: Teprotumumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Teprotumumab. •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): Teprotumumab is indicated for the treatment of thyroid eye disease regardless of disease activity or duration. •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): Teprotumumab inhibits the downstream effects of IGF-1R signaling, namely tissue inflammation and remodeling, which are responsible for the various symptoms of thyroid eye disease. Teprotumumab may cause disease flares in patients with pre-existing inflammatory bowel disease (IBD) - patients experiencing an exacerbation should discontinue therapy with teprotumumab. Significant hyperglycemia has been observed in patients receiving treatment with teprotumumab which may require antihyperglycemic medications. Based on its mechanism of action, it is likely that teprotumumab will cause fetal harm in pregnant woman - for this reason, females of child-bearing age should use effective contraception prior to initiation, during therapy, and for 6 months following the last dose of teprotumumab. •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): Graves’ Disease is an autoimmune syndrome involving the thyroid, orbital connective tissues, and some regions of the skin. One manifestation of Graves’ Disease is thyroid-associated ophthalmopathy, or thyroid eye disease, which is characterized by orbital inflammation, tissue remodeling, and fibrosis. As the disease progresses, patients may develop proptosis, strabismus, corneal ulceration, and optic neuropathy. It has been demonstrated that insulin-like growth factor-1 receptors (IGF-1R) are overexpressed by orbital fibroblasts in patients with thyroid eye disease, in addition to being overexpressed on T-cells and B-cells in these patients. It was found that Graves’ Disease IgG molecules could mimic the principal ligand of IGF-1R, insulin-like growth factor-1 (IGF-1), and their binding of IGF-1R induces the expression of chemokines that play roles in tissue remodeling and inflammation. For these reasons, IGF-1R was sought after as a potential therapeutic target for the treatment of thyroid eye disease. Teprotumumab is a fully human IgG1 monoclonal antibody directed against IGF-1R. It binds to and induces internalization and degradation of these receptors, thus preventing their downstream effects and alleviating symptoms of thyroid eye disease. •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 population of 40 patients receiving standard dosing in two clinical trials of teprotumumab, utilizing a two-compartment pharmacokinetic model, the AUC and C max were estimated to be 138 ± 34 mg•hr/mL and 632 ± 139 mcg/mL, 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): Following the standard dosing regimen, the mean central and peripheral volumes of distribution are approximately 3.26 ± 0.87 L and 4.32 ± 0.67 L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding teprotumumab serum protein binding is unavailable at this time. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of teprotumumab has not been fully characterized. As a protein, its metabolism is expected to involve proteolysis to smaller proteins and peptides. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Data regarding specific route(s) of elimination are unavailable at this time. •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 teprotumumab is 20 ± 5 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 estimated mean clearance of teprotumumab is 0.27 L/day. The inter-compartment clearance is 0.74 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): Toxicity information, including information regarding overdosage, is currently unavailable. Symptoms of teprotumumab overdose are likely to be consistent with its adverse effect profile. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tepezza •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): Teprotumumab is a fully human monoclonal antibody directed against insulin-like growth factor-1 receptor for the treatment of thyroid eye disease.

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 Teprotumumab interact? Information: •Drug A: Adalimumab •Drug B: Teprotumumab •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Teprotumumab. •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): Teprotumumab is indicated for the treatment of thyroid eye disease regardless of disease activity or duration. •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): Teprotumumab inhibits the downstream effects of IGF-1R signaling, namely tissue inflammation and remodeling, which are responsible for the various symptoms of thyroid eye disease. Teprotumumab may cause disease flares in patients with pre-existing inflammatory bowel disease (IBD) - patients experiencing an exacerbation should discontinue therapy with teprotumumab. Significant hyperglycemia has been observed in patients receiving treatment with teprotumumab which may require antihyperglycemic medications. Based on its mechanism of action, it is likely that teprotumumab will cause fetal harm in pregnant woman - for this reason, females of child-bearing age should use effective contraception prior to initiation, during therapy, and for 6 months following the last dose of teprotumumab. •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): Graves’ Disease is an autoimmune syndrome involving the thyroid, orbital connective tissues, and some regions of the skin. One manifestation of Graves’ Disease is thyroid-associated ophthalmopathy, or thyroid eye disease, which is characterized by orbital inflammation, tissue remodeling, and fibrosis. As the disease progresses, patients may develop proptosis, strabismus, corneal ulceration, and optic neuropathy. It has been demonstrated that insulin-like growth factor-1 receptors (IGF-1R) are overexpressed by orbital fibroblasts in patients with thyroid eye disease, in addition to being overexpressed on T-cells and B-cells in these patients. It was found that Graves’ Disease IgG molecules could mimic the principal ligand of IGF-1R, insulin-like growth factor-1 (IGF-1), and their binding of IGF-1R induces the expression of chemokines that play roles in tissue remodeling and inflammation. For these reasons, IGF-1R was sought after as a potential therapeutic target for the treatment of thyroid eye disease. Teprotumumab is a fully human IgG1 monoclonal antibody directed against IGF-1R. It binds to and induces internalization and degradation of these receptors, thus preventing their downstream effects and alleviating symptoms of thyroid eye disease. •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 population of 40 patients receiving standard dosing in two clinical trials of teprotumumab, utilizing a two-compartment pharmacokinetic model, the AUC and C max were estimated to be 138 ± 34 mg•hr/mL and 632 ± 139 mcg/mL, 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): Following the standard dosing regimen, the mean central and peripheral volumes of distribution are approximately 3.26 ± 0.87 L and 4.32 ± 0.67 L, respectively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding teprotumumab serum protein binding is unavailable at this time. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolism of teprotumumab has not been fully characterized. As a protein, its metabolism is expected to involve proteolysis to smaller proteins and peptides. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Data regarding specific route(s) of elimination are unavailable at this time. •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 teprotumumab is 20 ± 5 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 estimated mean clearance of teprotumumab is 0.27 L/day. The inter-compartment clearance is 0.74 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): Toxicity information, including information regarding overdosage, is currently unavailable. Symptoms of teprotumumab overdose are likely to be consistent with its adverse effect profile. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tepezza •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): Teprotumumab is a fully human monoclonal antibody directed against insulin-like growth factor-1 receptor for the treatment of thyroid eye disease. 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 Terbinafine interact?

•Drug A: Adalimumab •Drug B: Terbinafine •Severity: MODERATE •Description: The metabolism of Terbinafine 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): Terbinafine hydrochloride is indicated to treat fungal skin and nail infections caused by Trichophyton species, Microsporum canis, Epidermophyton floccosum, and Tinea species. Terbinafine hydrochloride also treats yeast infections of the skin caused by Candida species and Malassezia furfur. •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): Terbinafine is an allylamine antifungal that inhibits squalene epoxidase (also known as squalene monooxygenase) to prevent the formation of ergosterol and cause an accumulation of squalene, weakening the cell wall of fungal cells. Terbinafine distributes into tissues and has a long terminal elimination half life, so the duration of action is long. Overdose with terbinafine is rare, even above the therapeutic dose, so the therapeutic index is wide. Patients taking oral terbinafine should have liver function tests performed prior to treatment to reduce the risk of liver injury. •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): Terbinafine inhibits the enzyme squalene monooxygenase (also called squalene epoxidase), preventing the conversion of squalene to 2,3-oxydosqualene, a step in the synthesis of ergosterol. This inhibition leads to decreased ergosterol, which would normally be incorporated into the cell wall, and accumulation of squalene. Generation of a large number of squalene containing vesicles in the cytoplasm may leach other lipids away from, and further weaken, the cell wall. •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 terbinafine is >70% absorbed but only 40% bioavailable after first pass metabolism, reaching a C max of 1µg/mL with a T max of 2 hours an an AUC of 4.56µg*h/mL. Over the course of a week, 1% topical terbinafine's C max increases from 949-1049ng/cm and the AUC increases from 9694-13,492ng/cm /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): A single 250mg oral dose of terbinafine has a volume of distribution at steady state of 947.5L or 16.6L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Terbinafine is >99% bound to proteins in plasma, mostly to serum albumin, high and low density lipoproteins, and alpha-1-acid glycoprotein to a lesser extent. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Terbinafine can be deaminated to 1-naphthaldehyde by CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19. 1-naphthaldehyde is then oxidized to 1-naphthoic acid or reduced to 1-naphthalenemethanol. Terbinafine can also be hydroxylated by CYP1A2, 2C9, 2C8, 2B6, and 2C19 to hydroxyterbinafine. Hydroxyterbinafine is then oxidized to carboxyterbinafine or N-demethylated by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19 to desmethylhydroxyterbinafine. Terbinafine can be N-demethylated to desmethylterbinafine. Desmethylterbinafine is then dihydroxylated to a desmethyldihydrodiol or hydroxylated to desmethylhydroxyterbinafine. Finally, terbinafine can be dihydroxylated to a dihydrodiol which is then N-demethylated to a desmethyldihydrodiol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Terbinafine is approximately 80% eliminated in urine, while the remainder is eliminated in feces. The unmetabolized parent drug is not present 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): Oral terbinafine has an effective half life of approximately 36 hours. However, the terminal half life ranges from 200-400 hours as it distributes into skin and adipose tissue. 1% topical terbinafine's half life increases over the first seven days from approximately 10-40 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): A single 250mg oral dose of terbinafine has a clearance of 76L/h or 1.11L/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 subcutaneous LD 50 in rats and mice is >2g/kg. The TDLO for women is 210mg/kg/6W. Overdose data with terbinafine is rare, however symptoms are expected to be nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache. Treat overdose with activated charcoal as well as symptomatic and supportive therapy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lamisil, Silka Cream •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Terbinafina Terbinafine Terbinafinum •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): Terbinafine is an allylamine antifungal used to treat dermatophyte infections of toenails and fingernails as well as other fungal skin 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 CYP1A2 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Terbinafine interact? Information: •Drug A: Adalimumab •Drug B: Terbinafine •Severity: MODERATE •Description: The metabolism of Terbinafine 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): Terbinafine hydrochloride is indicated to treat fungal skin and nail infections caused by Trichophyton species, Microsporum canis, Epidermophyton floccosum, and Tinea species. Terbinafine hydrochloride also treats yeast infections of the skin caused by Candida species and Malassezia furfur. •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): Terbinafine is an allylamine antifungal that inhibits squalene epoxidase (also known as squalene monooxygenase) to prevent the formation of ergosterol and cause an accumulation of squalene, weakening the cell wall of fungal cells. Terbinafine distributes into tissues and has a long terminal elimination half life, so the duration of action is long. Overdose with terbinafine is rare, even above the therapeutic dose, so the therapeutic index is wide. Patients taking oral terbinafine should have liver function tests performed prior to treatment to reduce the risk of liver injury. •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): Terbinafine inhibits the enzyme squalene monooxygenase (also called squalene epoxidase), preventing the conversion of squalene to 2,3-oxydosqualene, a step in the synthesis of ergosterol. This inhibition leads to decreased ergosterol, which would normally be incorporated into the cell wall, and accumulation of squalene. Generation of a large number of squalene containing vesicles in the cytoplasm may leach other lipids away from, and further weaken, the cell wall. •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 terbinafine is >70% absorbed but only 40% bioavailable after first pass metabolism, reaching a C max of 1µg/mL with a T max of 2 hours an an AUC of 4.56µg*h/mL. Over the course of a week, 1% topical terbinafine's C max increases from 949-1049ng/cm and the AUC increases from 9694-13,492ng/cm /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): A single 250mg oral dose of terbinafine has a volume of distribution at steady state of 947.5L or 16.6L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Terbinafine is >99% bound to proteins in plasma, mostly to serum albumin, high and low density lipoproteins, and alpha-1-acid glycoprotein to a lesser extent. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Terbinafine can be deaminated to 1-naphthaldehyde by CYP2C9, 2B6, 2C8, 1A2, 3A4, and 2C19. 1-naphthaldehyde is then oxidized to 1-naphthoic acid or reduced to 1-naphthalenemethanol. Terbinafine can also be hydroxylated by CYP1A2, 2C9, 2C8, 2B6, and 2C19 to hydroxyterbinafine. Hydroxyterbinafine is then oxidized to carboxyterbinafine or N-demethylated by CYP3A4, 2B6, 1A2, 2C9, 2C8, and 2C19 to desmethylhydroxyterbinafine. Terbinafine can be N-demethylated to desmethylterbinafine. Desmethylterbinafine is then dihydroxylated to a desmethyldihydrodiol or hydroxylated to desmethylhydroxyterbinafine. Finally, terbinafine can be dihydroxylated to a dihydrodiol which is then N-demethylated to a desmethyldihydrodiol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Terbinafine is approximately 80% eliminated in urine, while the remainder is eliminated in feces. The unmetabolized parent drug is not present 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): Oral terbinafine has an effective half life of approximately 36 hours. However, the terminal half life ranges from 200-400 hours as it distributes into skin and adipose tissue. 1% topical terbinafine's half life increases over the first seven days from approximately 10-40 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): A single 250mg oral dose of terbinafine has a clearance of 76L/h or 1.11L/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 subcutaneous LD 50 in rats and mice is >2g/kg. The TDLO for women is 210mg/kg/6W. Overdose data with terbinafine is rare, however symptoms are expected to be nausea, vomiting, abdominal pain, dizziness, rash, frequent urination, and headache. Treat overdose with activated charcoal as well as symptomatic and supportive therapy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lamisil, Silka Cream •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Terbinafina Terbinafine Terbinafinum •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): Terbinafine is an allylamine antifungal used to treat dermatophyte infections of toenails and fingernails as well as other fungal skin 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 CYP1A2 substrates. The severity of the interaction is moderate.

Does Adalimumab and Terfenadine interact?

•Drug A: Adalimumab •Drug B: Terfenadine •Severity: MODERATE •Description: The metabolism of Terfenadine 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 allergic rhinitis, hay fever, and allergic skin 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): Terfenadine, an H1-receptor antagonist antihistamine, is similar in structure to astemizole and haloperidol, a butyrophenone antipsychotic. The active metabolite of terfenadine is fexofenadine. •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): Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal. •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): On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% •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): 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): 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): Mild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported. LD 50 =mg/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): Terfenadin Terfenadina Terfénadine Terfenadine Terfenadinum •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): Terfenadine is an antihistamine for the treatment of allergy symptoms.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Terfenadine interact? Information: •Drug A: Adalimumab •Drug B: Terfenadine •Severity: MODERATE •Description: The metabolism of Terfenadine 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 allergic rhinitis, hay fever, and allergic skin 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): Terfenadine, an H1-receptor antagonist antihistamine, is similar in structure to astemizole and haloperidol, a butyrophenone antipsychotic. The active metabolite of terfenadine is fexofenadine. •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): Terfenadine competes with histamine for binding at H1-receptor sites in the GI tract, uterus, large blood vessels, and bronchial muscle. This reversible binding of terfenadine to H1-receptors suppresses the formation of edema, flare, and pruritus resulting from histaminic activity. As the drug does not readily cross the blood-brain barrier, CNS depression is minimal. •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): On the basis of a mass balance study using 14C labeled terfenadine the oral absorption of terfenadine was estimated to be at least 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): No volume of distribution available •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 70% •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): 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): 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): Mild (e.g., headache, nausea, confusion), but adverse cardiac events including cardiac arrest, ventricular arrhythmias including torsades de pointes and QT prolongation have been reported. LD 50 =mg/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): Terfenadin Terfenadina Terfénadine Terfenadine Terfenadinum •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): Terfenadine is an antihistamine for the treatment of allergy symptoms. 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 Teriflunomide interact?

•Drug A: Adalimumab •Drug B: Teriflunomide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Teriflunomide. •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 the treatment of relapsing forms of multiple sclerosis (MS). •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): Teriflunomide is an immunomodulatory agent that decreases the amount of activated CNS lymphocytes, which results in anti-inflammatory and antiproliferative 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): The exact mechanism by which teriflunomide acts in MS is not known. What is known is that teriflunomide prevents pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, and this may be involved in its immunomodulatory effect in MS. •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 teriflunomide, maximum plasma concentrations are reached, on average, in 1-4 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): After a single intravenous dose, the volume of distribution is 11 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Teriflunomide is extensively plasma protein bound(>99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Teriflunomide mainly undergoes hydrolyis to minor metabolites. Other minor metabolic pathways include oxidation, N-acetylation and sulfate conjugation. Teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Teriflunomide is eliminated unchanged and mainly through bile. Specifically 37.5% is eliminated in the feces and 22.6% 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 median half-life is 18 to 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): After a single IV dose, teriflunomide has a total body clearance of 30.5 mL/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): Teriflunomide is contraindicated in pregnant women or women of childbearing age due to the risk of teratogenicity. Teriflunomide is also contraindicated in severe hepatic impairment due to reports of hepatotoxicity, hepatic failure, and death. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aubagio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teriflunomida Tériflunomide Teriflunomide Teriflunomidum •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): Teriflunomide is a pyrimidine synthesis inhibitor with anti-inflammatory and immunomodulatory properties used to treat patients with the relapsing-remitting form of multiple sclerosis.

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 Teriflunomide interact? Information: •Drug A: Adalimumab •Drug B: Teriflunomide •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Teriflunomide. •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 the treatment of relapsing forms of multiple sclerosis (MS). •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): Teriflunomide is an immunomodulatory agent that decreases the amount of activated CNS lymphocytes, which results in anti-inflammatory and antiproliferative 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): The exact mechanism by which teriflunomide acts in MS is not known. What is known is that teriflunomide prevents pyrimidine synthesis by inhibiting the mitochondrial enzyme dihydroorotate dehydrogenase, and this may be involved in its immunomodulatory effect in MS. •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 teriflunomide, maximum plasma concentrations are reached, on average, in 1-4 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): After a single intravenous dose, the volume of distribution is 11 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Teriflunomide is extensively plasma protein bound(>99%). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Teriflunomide mainly undergoes hydrolyis to minor metabolites. Other minor metabolic pathways include oxidation, N-acetylation and sulfate conjugation. Teriflunomide is not metabolized by CYP450 or flavin monoamine oxidase. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Teriflunomide is eliminated unchanged and mainly through bile. Specifically 37.5% is eliminated in the feces and 22.6% 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 median half-life is 18 to 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): After a single IV dose, teriflunomide has a total body clearance of 30.5 mL/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): Teriflunomide is contraindicated in pregnant women or women of childbearing age due to the risk of teratogenicity. Teriflunomide is also contraindicated in severe hepatic impairment due to reports of hepatotoxicity, hepatic failure, and death. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aubagio •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teriflunomida Tériflunomide Teriflunomide Teriflunomidum •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): Teriflunomide is a pyrimidine synthesis inhibitor with anti-inflammatory and immunomodulatory properties used to treat patients with the relapsing-remitting form of multiple sclerosis. 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 Testosterone cypionate interact?

•Drug A: Adalimumab •Drug B: Testosterone cypionate •Severity: MODERATE •Description: The metabolism of Testosterone cypionate 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): Testosterone cypionate is used in males that present conditions derived from a deficiency or absence of endogenous testosterone. These conditions are 1) primary hypogonadism, defined as the testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; and 2) hypogonadotropic hypogonadism characterized by idiopathic gonadotropin, LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma or radiation. •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): Administration of ester derivatives of testosterone as testosterone cypionate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. The continuous variation in plasma testosterone after intramuscular administration of testosterone cypionate results in fluctuations in mood and libido as well as some local 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): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen 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): Testosterone cypionate is an esterified anabolic which allows it to present a greater degree of solubility in fats and thus, the release and absorption occur in a slow rate compare to homologous molecules. Intramuscular administration of 200 mg of testosterone cypionate produced a mean supratherapeutic Cmax of 1122 ng/dl which occurred 4-5 days post-injection. After the fifth day, the levels of testosterone cypionate in plasma went down reaching an average of 400 ng/dl. •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 following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone cypionate, following conversion into testosterone, is approximately 98% protein-bound to sex hormone-binding globulin in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): To start its activity, testosterone cypionate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the cypionate ester moiety and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated 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): The half-life of testosterone cypionate is one of the longest, being approximately of 8 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): Testosterone cypionate presents a lower clearance rate after intramuscular administration compared to other analogs of testosterone. •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): Preclinical studies with testosterone implants induced cervical-uterine tumors in mice which metastasized in some cases. Some reports indicate that administration of testosterone cypionate in females can augment the susceptibility to hepatoma as well as increase the number of tumors. Clinical studies have reported cases of hepatocellular carcinoma in long-term high-dose therapy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Depo-testosterone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosterone cipionate Testosterone cyclopentanepropionate Testosterone cyclopentylpropionate Testosterone cypionate •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): Testosterone cypionate is an androgen used to treat low or absent testosterone.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Testosterone cypionate interact? Information: •Drug A: Adalimumab •Drug B: Testosterone cypionate •Severity: MODERATE •Description: The metabolism of Testosterone cypionate 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): Testosterone cypionate is used in males that present conditions derived from a deficiency or absence of endogenous testosterone. These conditions are 1) primary hypogonadism, defined as the testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; and 2) hypogonadotropic hypogonadism characterized by idiopathic gonadotropin, LHRH deficiency or pituitary-hypothalamic injury from tumors, trauma or radiation. •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): Administration of ester derivatives of testosterone as testosterone cypionate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. The continuous variation in plasma testosterone after intramuscular administration of testosterone cypionate results in fluctuations in mood and libido as well as some local 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): The effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5-alpha-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5-alpha-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing the androgen 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): Testosterone cypionate is an esterified anabolic which allows it to present a greater degree of solubility in fats and thus, the release and absorption occur in a slow rate compare to homologous molecules. Intramuscular administration of 200 mg of testosterone cypionate produced a mean supratherapeutic Cmax of 1122 ng/dl which occurred 4-5 days post-injection. After the fifth day, the levels of testosterone cypionate in plasma went down reaching an average of 400 ng/dl. •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 following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone cypionate, following conversion into testosterone, is approximately 98% protein-bound to sex hormone-binding globulin in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): To start its activity, testosterone cypionate has to be processed by enzymes in the bloodstream. These enzymes will break the bond between the cypionate ester moiety and the testosterone. Once separated, testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated 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): The half-life of testosterone cypionate is one of the longest, being approximately of 8 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): Testosterone cypionate presents a lower clearance rate after intramuscular administration compared to other analogs of testosterone. •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): Preclinical studies with testosterone implants induced cervical-uterine tumors in mice which metastasized in some cases. Some reports indicate that administration of testosterone cypionate in females can augment the susceptibility to hepatoma as well as increase the number of tumors. Clinical studies have reported cases of hepatocellular carcinoma in long-term high-dose therapy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Depo-testosterone •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosterone cipionate Testosterone cyclopentanepropionate Testosterone cyclopentylpropionate Testosterone cypionate •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): Testosterone cypionate is an androgen used to treat low or absent testosterone. 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 Testosterone enanthate interact?

•Drug A: Adalimumab •Drug B: Testosterone enanthate •Severity: MODERATE •Description: The metabolism of Testosterone enanthate 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): Testosterone enanthate in males is indicated as a replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Some of the treated conditions are 1) primary hypogonadism, defined as testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; 2) hypogonadotropic hypogonadism due to an idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or due to a pituitary-hypothalamic injury from tumors, trauma or radiation, in this case it is important to accompany the treatment with adrenal cortical and thyroid hormone replacement therapy; 3) to stimulate puberty in patients with delayed puberty not secondary to a pathological disorder. If the conditions 1 and 2 occur prior to puberty, the androgen replacement therapy will be needed during adolescent years for the development of secondary sexual characteristics and prolonged androgen treatment might be needed it to maintain sexual characteristics after puberty. In females, testosterone enanthate is indicated to be used secondarily in presence of advanced inoperable metastatic mammary cancer in women who are from one to five years postmenopausal. It has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Testosterone enanthate injections that are currently formulated for subcutaneous use are specifically indicated only for primary hypogonadism and hypogonadotropic hypogonadism. The use of such formulations is limited because the safety and efficacy of these subcutaneous products in adult males with late-onset hypogonadism and males less than 18 years old have not yet been established. Moreover, subcutaneously administered testosterone enanthate is indicated only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies, considering the medication could cause blood pressure increases that can raise the risk of major adverse cardiovascular events like non-fatal myocardial infarction, non-fatal stroke, and cardiovascular 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): Administration of ester derivatives of testosterone as testosterone enanthate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. Continuous administration of testosterone enanthate shows a significant suppression of dihydrotestosterone, serum PSA, HDL and FSH, as well as a slight increase in serum estradiol. The levels of dihydrotestosterone and FSH can remain suppressed even 14 days after treatment termination. There are no changes in mood and sexual activity by the presence of testosterone enanthate. •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 effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing androgen effects. Such activities are useful as endogenous androgens like testosterone and dihydrotestosterone are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). •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 pharmacokinetic profile of testosterone enanthate was studied in a regime of multiple dosing and the testosterone level was reported to present a Cmax above 1200 ng/dl after 24 hours of the last dose. The concentration decreased sequentially until it reached 600 ng/dl after one week. The pharmacokinetic profile of testosterone enanthate presented differences depending on the administered dose in which the tmax was shifted to a range of 36-48 hours. The plasma testosterone level plateaued below the therapeutic range after 3-4 weeks. This reports showed that the different formulation of testosterone enanthate and testosterone cypionate generates a different profile and thus, they are not therapeutically equivalent. •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 following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 98% of testosterone in plasma is bound to SHBG while 2% remains unbound (i.e. free). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): To start its activity, testosterone enanthate has to be processed by enzymes in the bloodstream. These enzymes will catalyze the molecule at the ester location of the moiety. Once processed in this manner, the testosterone enanthate molecule is metabolized to various 17-keto steroids through two different pathways. Subsequently, the major active metabolites are estradiol and DHTd. Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. The inactivation of testosterone occurs primarily in the liver. •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): Testosterone enanthate presents a long half-life in the range of 7-9 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): 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): Testosterone enanthate has been tested in preclinical carcinogenesis trials. In this studies, it is suggested that the exposure to this drug may increase the susceptibility to hematoma as well as the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver. Testosterone enanthate is not indicated for use in females and is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action. During treatment with large doses of exogenous androgens, including testosterone enanthate, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis. Reduced fertility is observed in some men taking testosterone replacement therapy and the impact on fertility may be irreversible. Safety and effectiveness of testosterone enanthate in pediatric patients less than 18 years old have not been established. Improper use may result in the acceleration of bone age and premature closure of epiphyses. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of Benign Prostatic Hyperplasia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Delatestryl, Xyosted •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): Testosterone enanthate is an androgen used to treat low or absent testosterone.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Testosterone enanthate interact? Information: •Drug A: Adalimumab •Drug B: Testosterone enanthate •Severity: MODERATE •Description: The metabolism of Testosterone enanthate 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): Testosterone enanthate in males is indicated as a replacement therapy in conditions associated with a deficiency or absence of endogenous testosterone. Some of the treated conditions are 1) primary hypogonadism, defined as testicular failure due to cryptorchidism, bilateral torsion, orchitis, vanishing testis syndrome or orchidectomy; 2) hypogonadotropic hypogonadism due to an idiopathic gonadotropin or luteinizing hormone-releasing hormone deficiency or due to a pituitary-hypothalamic injury from tumors, trauma or radiation, in this case it is important to accompany the treatment with adrenal cortical and thyroid hormone replacement therapy; 3) to stimulate puberty in patients with delayed puberty not secondary to a pathological disorder. If the conditions 1 and 2 occur prior to puberty, the androgen replacement therapy will be needed during adolescent years for the development of secondary sexual characteristics and prolonged androgen treatment might be needed it to maintain sexual characteristics after puberty. In females, testosterone enanthate is indicated to be used secondarily in presence of advanced inoperable metastatic mammary cancer in women who are from one to five years postmenopausal. It has also been used in premenopausal women with breast cancer who have benefited from oophorectomy and are considered to have a hormone-responsive tumor. Testosterone enanthate injections that are currently formulated for subcutaneous use are specifically indicated only for primary hypogonadism and hypogonadotropic hypogonadism. The use of such formulations is limited because the safety and efficacy of these subcutaneous products in adult males with late-onset hypogonadism and males less than 18 years old have not yet been established. Moreover, subcutaneously administered testosterone enanthate is indicated only for the treatment of men with hypogonadal conditions associated with structural or genetic etiologies, considering the medication could cause blood pressure increases that can raise the risk of major adverse cardiovascular events like non-fatal myocardial infarction, non-fatal stroke, and cardiovascular 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): Administration of ester derivatives of testosterone as testosterone enanthate generates an increase in serum testosterone to levels reaching 400% from the baseline within 24 hours of administration. These androgen levels remain elevated for 3-5 days after initial administration. Continuous administration of testosterone enanthate shows a significant suppression of dihydrotestosterone, serum PSA, HDL and FSH, as well as a slight increase in serum estradiol. The levels of dihydrotestosterone and FSH can remain suppressed even 14 days after treatment termination. There are no changes in mood and sexual activity by the presence of testosterone enanthate. •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 effects of testosterone in humans and other vertebrates occur by way of two main mechanisms: by activation of the androgen receptor (directly or as DHT), and by conversion to estradiol and activation of certain estrogen receptors. Free testosterone (T) is transported into the cytoplasm of target tissue cells, where it can bind to the androgen receptor, or can be reduced to 5α-dihydrotestosterone (DHT) by the cytoplasmic enzyme 5α-reductase. DHT binds to the same androgen receptor even more strongly than T, so that its androgenic potency is about 2.5 times that of T. The T-receptor or DHT-receptor complex undergoes a structural change that allows it to move into the cell nucleus and bind directly to specific nucleotide sequences of the chromosomal DNA. The areas of binding are called hormone response elements (HREs), and influence transcriptional activity of certain genes, producing androgen effects. Such activities are useful as endogenous androgens like testosterone and dihydrotestosterone are responsible for the normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include the growth and maturation of the prostate, seminal vesicles, penis, and scrotum; the development of male hair distribution, such as facial, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter’s syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH). •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 pharmacokinetic profile of testosterone enanthate was studied in a regime of multiple dosing and the testosterone level was reported to present a Cmax above 1200 ng/dl after 24 hours of the last dose. The concentration decreased sequentially until it reached 600 ng/dl after one week. The pharmacokinetic profile of testosterone enanthate presented differences depending on the administered dose in which the tmax was shifted to a range of 36-48 hours. The plasma testosterone level plateaued below the therapeutic range after 3-4 weeks. This reports showed that the different formulation of testosterone enanthate and testosterone cypionate generates a different profile and thus, they are not therapeutically equivalent. •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 following intravenous administration of testosterone is of approximately 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Circulating testosterone is primarily bound in serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 98% of testosterone in plasma is bound to SHBG while 2% remains unbound (i.e. free). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): To start its activity, testosterone enanthate has to be processed by enzymes in the bloodstream. These enzymes will catalyze the molecule at the ester location of the moiety. Once processed in this manner, the testosterone enanthate molecule is metabolized to various 17-keto steroids through two different pathways. Subsequently, the major active metabolites are estradiol and DHTd. Testosterone is metabolized to DHT by steroid 5α-reductase in skin, liver and urogenital tract. In reproductive tissues DHT is further metabolized to androstanediol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 90% of a dose of testosterone given intramuscularly is excreted in the urine as glucuronic and sulfuric acid conjugates of testosterone and its metabolites; about 6% of a dose is excreted in the feces, mostly in the unconjugated form. The inactivation of testosterone occurs primarily in the liver. •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): Testosterone enanthate presents a long half-life in the range of 7-9 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): 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): Testosterone enanthate has been tested in preclinical carcinogenesis trials. In this studies, it is suggested that the exposure to this drug may increase the susceptibility to hematoma as well as the number of tumors and decrease the degree of differentiation of chemically induced carcinomas of the liver. Testosterone enanthate is not indicated for use in females and is contraindicated in pregnant women. Testosterone is teratogenic and may cause fetal harm when administered to a pregnant woman based on data from animal studies and its mechanism of action. During treatment with large doses of exogenous androgens, including testosterone enanthate, spermatogenesis may be suppressed through feedback inhibition of the hypothalamic-pituitary-testicular axis. Reduced fertility is observed in some men taking testosterone replacement therapy and the impact on fertility may be irreversible. Safety and effectiveness of testosterone enanthate in pediatric patients less than 18 years old have not been established. Improper use may result in the acceleration of bone age and premature closure of epiphyses. Geriatric patients treated with androgens may also be at risk for worsening of signs and symptoms of Benign Prostatic Hyperplasia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Delatestryl, Xyosted •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): Testosterone enanthate is an androgen used to treat low or absent testosterone. 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 Testosterone interact?

•Drug A: Adalimumab •Drug B: Testosterone •Severity: MODERATE •Description: The metabolism of Testosterone 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): Testosterone is indicated to treat primary hypogonadism and hypogonadotropic hypogonadism. •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): Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics. The duration of action of testosterone is variable from patient to patient with a half life of 10-100 minutes. The therapeutic index is wide considering the normal testosterone levels in an adult man range from 300-1000ng/dL. Counsel patients regarding the risk of secondary exposure of testosterone topical products to 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): The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes. Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum. Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution. •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 single 100mg topical dose of testosterone has an AUC of 10425±5521ng*h/dL and a C max of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically. •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 testosterone in elderly men is 80.36±24.51L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone is 40% bound to sex hormone binding globulin, 2% unbound, and the remainder is bound to albumin and other proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated 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 half life of testosterone is highly variable, ranging from 10-100 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 mean metabolic clearance in middle aged men is 812±64L/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 an overdose with a topical testosterone product is not readily available. In the case of overdose with an injectable product, patients may present with a cerebrovascular event. Treat overdoses by stopping testosterone products, washing off any topical products with soap and water, and initiating symptomatic and supportive treatments. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Testopel, Vogelxo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosteron Testosterona Testostérone Testosterone Testosteronum Virosterone •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): Testosterone is a hormone used to treat hypogonadism, breast carcinoma in women, or the vasomotor symptoms of menopause.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Testosterone interact? Information: •Drug A: Adalimumab •Drug B: Testosterone •Severity: MODERATE •Description: The metabolism of Testosterone 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): Testosterone is indicated to treat primary hypogonadism and hypogonadotropic hypogonadism. •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): Testosterone antagonizes the androgen receptor to induce gene expression that causes the growth and development of masculine sex organs and secondary sexual characteristics. The duration of action of testosterone is variable from patient to patient with a half life of 10-100 minutes. The therapeutic index is wide considering the normal testosterone levels in an adult man range from 300-1000ng/dL. Counsel patients regarding the risk of secondary exposure of testosterone topical products to 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): The androgen receptor exists in the cytoplasm bound to the heat shock proteins HSP90, HSP70, and other chaperones. After binding to an androgen, the androgen receptor dissociates from HSP90 and undergoes a conformational change to slow the rate of dissociation from the androgen receptor. The androgen-receptor complex is transported into the nucleus where it binds to DNA and recruits other transcriptional regulators to form a pre-initiation complex and eventually induce expression of specific genes. Testosterone and its active metabolite dihydrotestosterone (DHT) antagonize the androgen receptor to develop masculine sex organs including the prostate, seminal vesicles, penis, and scrotum. Antagonism of the androgen receptor is also responsible for the development of secondary sexual characteristics including facial and body hair, enlargement of the larynx, thickening of the vocal cords, and changes in muscle and fat distribution. •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 single 100mg topical dose of testosterone has an AUC of 10425±5521ng*h/dL and a C max of 573±284ng/dL. Testosterone is approximately 10% bioavailable topically. •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 testosterone in elderly men is 80.36±24.51L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Testosterone is 40% bound to sex hormone binding globulin, 2% unbound, and the remainder is bound to albumin and other proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Testosterone is metabolized to 17-keto steroids through two different pathways. The major active metabolites are estradiol and dihydrotestosterone (DHT). Testosterone can be hydroxylated at a number of positions by CYP3A4, CYP2B6, CYP2C9, and CYP2C19; glucuronidated by UGT2B17; sulfated; converted to estradiol by aromatase; converted to dihydrotestosterone (DHT) by 5α-reductase; metabolized to androstenedione by CYP3A4, CYP2C9, and CYP2C19; or converted to DHT glucuronide. Androstenedione undergoes metabolism by aromatase to form estrone, which undergoes a reversible reaction to form estradiol. Androstenedione can also be converted to 5α-androstanedione by 5α-reductase, which can be further metabolized to 5α-androsterone. DHT can be glucuronidated or sulfated, or metabolized to 5α-androstanediol, androstane-3α,17β-diol, or androstane-3β,17β-diol. DHT can also be reversibly converted to 5α-androstanedione. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 90% of an intramuscular dose is eliminated in urine, mainly as glucuronide and sulfate conjugates. 6% is eliminated in feces, mostly as unconjugated 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 half life of testosterone is highly variable, ranging from 10-100 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 mean metabolic clearance in middle aged men is 812±64L/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 an overdose with a topical testosterone product is not readily available. In the case of overdose with an injectable product, patients may present with a cerebrovascular event. Treat overdoses by stopping testosterone products, washing off any topical products with soap and water, and initiating symptomatic and supportive treatments. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Androderm, Androgel, Axiron, Fortesta, Natesto, Striant, Testim, Testopel, Vogelxo •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Testosteron Testosterona Testostérone Testosterone Testosteronum Virosterone •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): Testosterone is a hormone used to treat hypogonadism, breast carcinoma in women, or the vasomotor symptoms of menopause. 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 Tetanus immune globulin, human interact?

•Drug A: Adalimumab •Drug B: Tetanus immune globulin, human •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tetanus immune globulin, human. •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. •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

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 Tetanus immune globulin, human interact? Information: •Drug A: Adalimumab •Drug B: Tetanus immune globulin, human •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tetanus immune globulin, human. •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. •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: 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 Tetrabenazine interact?

•Drug A: Adalimumab •Drug B: Tetrabenazine •Severity: MODERATE •Description: The metabolism of Tetrabenazine 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): Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia •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): Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post 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): Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM). •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 administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients •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, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% 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): There is interindividual variability in elimination half-life. The elimination half-life of tetrabenazine was 10 hours following intravenous bolus administration. The oral half-lives of its metabolites, α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are seven hours, five hours and 12 hours, respectively. Following a single oral dose of 25 mg tetrabenazine, the elimination half-life was approximately 17.5 hours in subjects with 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): IV, 1.67 L/min in HD or tardive dyskinesia 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. •Toxicity (Drug B): Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Nitoman, Xenazine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tetrabenazina Tetrabenazine Tetrabenazinum •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): Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor used for the management of chorea associated with Huntington'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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Tetrabenazine interact? Information: •Drug A: Adalimumab •Drug B: Tetrabenazine •Severity: MODERATE •Description: The metabolism of Tetrabenazine 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): Treatment of hyperkinetic movement disorders like chorea in Huntington's disease, hemiballismus, senile chorea, Tourette syndrome and other tic disorders, and tardive dyskinesia •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): Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post 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): Tetrabenazine is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM). •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 administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients; Tmax, oral = 69 min in HD or tardive dyskinesia patients •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, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazine is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tetrabenazine = 82 - 88%; α-HTBZ = 60 - 68%; β-HTBZ = 59 - 63%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tetrabenazine is hepatically metabolized. Carbonyl reductase in the liver is responsible for the formation of two major active metabolites: α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). α-HTBZ is further metabolized into 9-desmethyl-α-DHTBZ, a minor metabolite by CYP2D6 and with some contribution of CYP1A2. β-HTBZ is metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, by CYP2D6. The Tmax of this metabolite is 2 hours post-administration of tetrabenazine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazine is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% 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): There is interindividual variability in elimination half-life. The elimination half-life of tetrabenazine was 10 hours following intravenous bolus administration. The oral half-lives of its metabolites, α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are seven hours, five hours and 12 hours, respectively. Following a single oral dose of 25 mg tetrabenazine, the elimination half-life was approximately 17.5 hours in subjects with 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): IV, 1.67 L/min in HD or tardive dyskinesia 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. •Toxicity (Drug B): Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Nitoman, Xenazine •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tetrabenazina Tetrabenazine Tetrabenazinum •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): Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor used for the management of chorea associated with Huntington'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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Tezepelumab interact?

•Drug A: Adalimumab •Drug B: Tezepelumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tezepelumab. •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): Tezepelumab is indicated as an add-on maintenance treatment for patients aged 12 years and older with severe asthma. In Europe, it is reserved for patients who are inadequately controlled despite maintenance treatment with high-dose inhaled corticosteroids plus another drug. Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus. •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): Tezepelumab is a human monoclonal IgG2λ antibody blocking thymic stromal lymphopoietin (TSLP). Tezepelumab treatment in asthmatic patients improves disease markers, including blood and airway submucosal eosinophils and IgE, FeNO, IL-5, and IL-13 levels. Despite an excellent safety profile, tezepelumab may be associated with hypersensitivity reactions and increased risk of infection, especially by parasitic helminths. Patients receiving tezepelumab should not discontinue systemic or inhaled corticosteroids, and any reduction in these drugs should be performed cautiously. •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): Asthma is a heterogeneous chronic obstructive respiratory disease characterized by reduced airflow, chronic inflammation, and airway remodelling. Generally, asthma can be divided into "type 2" (T2, including allergic and eosinophilic presentations) and T2-low (including neutrophilic and paucigranulocytic presentations) endotypes, each driven by distinct underlying pathways. Thymic stromal lymphopoietin (TSLP) is an innate pleiotropic IL-2-family cytokine distantly related to IL-7; two forms of TSLP exist, with a short isoform (sfTSLP, 60 amino acids long) and a long isoform (lfTSLP, 159 amino acids long). The short isoform appears to be constitutively expressed, especially by lung and gut epithelial cells, while lfTSLP is upregulated in response to proinflammatory stimuli. While the role of sfTSLP is still unclear, lfTSLP has emerged as an upstream alarmin central to the pathophysiology of inflammatory disorders including asthma, atopic rhinitis, chronic obstructive pulmonary disease, eosinophilic esophagitis, and atopic dermatitis. Under normal conditions, lfTSLP interacts with its cognate receptor TSLPR, and IL-7Rα in a ternary complex with three contact sites labelled site I (TSLP:TSLPR), site II (TSLP:IL-7Rα), and site III (TSLPR:IL-7Rα). The assembly of the ternary complex is stepwise, as TSLP does not interact appreciably with IL-7Rα until after it has bound TSLPR. Complementary electrostatic surfaces on TSLP and TSLPR mediate initial high affinity formation of a TSLP:TSLPR complex ( K D of 32 nM and k a of 1.7 x 10 M s ). This initial binding induces a restructuring of the π-helical turn in the TSLP αA helix and structuring of the AB loop to facilitate binding of TSLP to a hydrophobic patch on IL-7Rα to form the ternary complex ( K D of 29 nM and k a of 1.23 x 10 M s ). The complete ternary complex is stabilized by additional interactions between TSLPR and IL-7Rα at site III near the transmembrane domain of each receptor. Formation of the ternary complex activates JAK1/2, which, through downstream pathways involving STAT3/5, NF-κB, PI3K, and MAPK, induces the expression of Th2 cytokines including IL-4, IL-5, IL-9, and IL-13. TSLP can induce Th2 cytokine production by stimulating dendritic cells and ILC2 cells (primarily in T2 asthma). Furthermore, TSLP has been implicated in steroid resistance of ILC2 cells. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of Th17 cells, which secrete IL-17A to recruit neutrophils and drive inflammation. In paucigranulocytic asthma, TSLP mediates cross-talk between mast cells, smooth muscle cells, and fibroblasts. Hence, despite different underlying pathways, TSLP appears to function as a critical upstream driver across asthma endotypes. Tezepelumab is a human monoclonal IgG2λ antibody that binds to TSLP with a dissociation constant of 15.8 pM. Specifically, the variable heavy chain domain (V H ) complementarity determining regions (CDRs) of tezepelumab bind TSLP at the AB -loop region and C-terminal region of the αD helix, obstructing the TSLPR binding region while leaving the IL-7Rα binding region unobstructed. As TSLP is incapable of binding IL-7Rα prior to its inclusion in the TSLP:TSLPR dimer, tezepelumab effectively blocks the assembly of the ternary complex and resulting downstream signalling. Furthermore, unlike existing therapies that act on specific downstream effector molecules, targeting TSLP ensures effective upstream blockade and is expected to be efficacious against multiple asthma endotypes. •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 subcutaneously, tezepelumab reaches C max in approximately 3-10 days with an estimated absolute bioavailability of 77%, regardless of injection site choice. Tezepelumab displays dose-proportional pharmacokinetics over a range of 2.1-420 mg (0.01-2 times the recommended dose) following a single subcutaneous dose. With a 4-week dosing schedule, tezepelumab achieves steady-state kinetics after 12 weeks with a 1.86-fold C trough accumulation ratio. There are no clinically meaningful changes expected for tezepelumab pharmacokinetics in patients across patient populations, including those with renal or hepatic impairment. •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): Tezepelumab has a central V d of 3.9 L and a peripheral V d of 2.2 L (for a 70 kg individual). •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): As a human monoclonal antibody, tezepelumab is expected to be degraded by various proteolytic enzymes throughout the body. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As a human monoclonal antibody, tezepelumab is eliminated primarily through catabolism; there is no evidence of target-mediated clearance at the therapeutic 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): Tezepelumab has an elimination half-life of ~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): Tezepelumab has an estimated clearance of 0.17 L/d (for a 70 kg individual). •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 regarding tezepelumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as opportunistic infections and other conditions related to immunosuppression. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tezspire •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): Tezepelumab is a human monoclonal IgG2λ thymic stromal lymphopoietin (TSLP)-blocking antibody for add-on maintenance therapy in severe asthma.

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 Tezepelumab interact? Information: •Drug A: Adalimumab •Drug B: Tezepelumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tezepelumab. •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): Tezepelumab is indicated as an add-on maintenance treatment for patients aged 12 years and older with severe asthma. In Europe, it is reserved for patients who are inadequately controlled despite maintenance treatment with high-dose inhaled corticosteroids plus another drug. Tezepelumab is not indicated for the relief of acute bronchospasm or status asthmaticus. •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): Tezepelumab is a human monoclonal IgG2λ antibody blocking thymic stromal lymphopoietin (TSLP). Tezepelumab treatment in asthmatic patients improves disease markers, including blood and airway submucosal eosinophils and IgE, FeNO, IL-5, and IL-13 levels. Despite an excellent safety profile, tezepelumab may be associated with hypersensitivity reactions and increased risk of infection, especially by parasitic helminths. Patients receiving tezepelumab should not discontinue systemic or inhaled corticosteroids, and any reduction in these drugs should be performed cautiously. •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): Asthma is a heterogeneous chronic obstructive respiratory disease characterized by reduced airflow, chronic inflammation, and airway remodelling. Generally, asthma can be divided into "type 2" (T2, including allergic and eosinophilic presentations) and T2-low (including neutrophilic and paucigranulocytic presentations) endotypes, each driven by distinct underlying pathways. Thymic stromal lymphopoietin (TSLP) is an innate pleiotropic IL-2-family cytokine distantly related to IL-7; two forms of TSLP exist, with a short isoform (sfTSLP, 60 amino acids long) and a long isoform (lfTSLP, 159 amino acids long). The short isoform appears to be constitutively expressed, especially by lung and gut epithelial cells, while lfTSLP is upregulated in response to proinflammatory stimuli. While the role of sfTSLP is still unclear, lfTSLP has emerged as an upstream alarmin central to the pathophysiology of inflammatory disorders including asthma, atopic rhinitis, chronic obstructive pulmonary disease, eosinophilic esophagitis, and atopic dermatitis. Under normal conditions, lfTSLP interacts with its cognate receptor TSLPR, and IL-7Rα in a ternary complex with three contact sites labelled site I (TSLP:TSLPR), site II (TSLP:IL-7Rα), and site III (TSLPR:IL-7Rα). The assembly of the ternary complex is stepwise, as TSLP does not interact appreciably with IL-7Rα until after it has bound TSLPR. Complementary electrostatic surfaces on TSLP and TSLPR mediate initial high affinity formation of a TSLP:TSLPR complex ( K D of 32 nM and k a of 1.7 x 10 M s ). This initial binding induces a restructuring of the π-helical turn in the TSLP αA helix and structuring of the AB loop to facilitate binding of TSLP to a hydrophobic patch on IL-7Rα to form the ternary complex ( K D of 29 nM and k a of 1.23 x 10 M s ). The complete ternary complex is stabilized by additional interactions between TSLPR and IL-7Rα at site III near the transmembrane domain of each receptor. Formation of the ternary complex activates JAK1/2, which, through downstream pathways involving STAT3/5, NF-κB, PI3K, and MAPK, induces the expression of Th2 cytokines including IL-4, IL-5, IL-9, and IL-13. TSLP can induce Th2 cytokine production by stimulating dendritic cells and ILC2 cells (primarily in T2 asthma). Furthermore, TSLP has been implicated in steroid resistance of ILC2 cells. In neutrophilic asthma, TSLP induces dendritic cells to drive the development of Th17 cells, which secrete IL-17A to recruit neutrophils and drive inflammation. In paucigranulocytic asthma, TSLP mediates cross-talk between mast cells, smooth muscle cells, and fibroblasts. Hence, despite different underlying pathways, TSLP appears to function as a critical upstream driver across asthma endotypes. Tezepelumab is a human monoclonal IgG2λ antibody that binds to TSLP with a dissociation constant of 15.8 pM. Specifically, the variable heavy chain domain (V H ) complementarity determining regions (CDRs) of tezepelumab bind TSLP at the AB -loop region and C-terminal region of the αD helix, obstructing the TSLPR binding region while leaving the IL-7Rα binding region unobstructed. As TSLP is incapable of binding IL-7Rα prior to its inclusion in the TSLP:TSLPR dimer, tezepelumab effectively blocks the assembly of the ternary complex and resulting downstream signalling. Furthermore, unlike existing therapies that act on specific downstream effector molecules, targeting TSLP ensures effective upstream blockade and is expected to be efficacious against multiple asthma endotypes. •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 subcutaneously, tezepelumab reaches C max in approximately 3-10 days with an estimated absolute bioavailability of 77%, regardless of injection site choice. Tezepelumab displays dose-proportional pharmacokinetics over a range of 2.1-420 mg (0.01-2 times the recommended dose) following a single subcutaneous dose. With a 4-week dosing schedule, tezepelumab achieves steady-state kinetics after 12 weeks with a 1.86-fold C trough accumulation ratio. There are no clinically meaningful changes expected for tezepelumab pharmacokinetics in patients across patient populations, including those with renal or hepatic impairment. •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): Tezepelumab has a central V d of 3.9 L and a peripheral V d of 2.2 L (for a 70 kg individual). •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): As a human monoclonal antibody, tezepelumab is expected to be degraded by various proteolytic enzymes throughout the body. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): As a human monoclonal antibody, tezepelumab is eliminated primarily through catabolism; there is no evidence of target-mediated clearance at the therapeutic 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): Tezepelumab has an elimination half-life of ~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): Tezepelumab has an estimated clearance of 0.17 L/d (for a 70 kg individual). •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 regarding tezepelumab is not readily available. Patients experiencing an overdose are at an increased risk of severe adverse effects such as opportunistic infections and other conditions related to immunosuppression. Symptomatic and supportive measures are recommended. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tezspire •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): Tezepelumab is a human monoclonal IgG2λ thymic stromal lymphopoietin (TSLP)-blocking antibody for add-on maintenance therapy in severe asthma. 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 Thalidomide interact?

•Drug A: Adalimumab •Drug B: Thalidomide •Severity: MODERATE •Description: The metabolism of Thalidomide 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): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •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): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •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 thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •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 has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL 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): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •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 thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 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): The oral clearance of thalidomide is 10.50 ± 2.10 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 LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Talidomida Thalidomide Thalidomidum •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): Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Thalidomide interact? Information: •Drug A: Adalimumab •Drug B: Thalidomide •Severity: MODERATE •Description: The metabolism of Thalidomide 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): Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). •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): Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (−)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans. •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 thalidomide is not fully understood. Previous research indicate that thalidomide binds to cerebron, a component of the E3 ubiquitin ligase complex, to selectively degrade the transcription factor IKZF3 and IKZF1. These 2 transcription factors are vital for the proliferation and survival of malignant myeloma cells. Regarding TNF-alpha, thalidomide seems to block this mediator via a variety of mechanism. Thalidomide can inhibit the expression myeloid differentiating factor 88 (MyD88), an adaptor protein that is involved in the TNF-alpha production signalling pathway, at the protein and RNA level. Additionally, thalidomide prevents the activation of Nuclear Factor Kappa B (NF-kB), another upstream effector of the TNF-alpha production pathway. Finally, some evidences suggest that thalidomide can block alpha-1 acid glycoprotein (AGP), a known inducer of the NF-kB/MyD88 pathway, thus inhibiting the expression of TNF-alpha. The down-regulation of NF-kB and MyD88 can also affect the cross talk between the NF-kB/MyD88 and VEGF pathway, resulting in thalidomide's anti-angiogenic effect. •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 has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (T max ) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown. Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a t lag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, c max and AUC ∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL 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): The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The mean plasma protein binding is 55% and 66% for the (+)R and (−)S enantiomers, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH. Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal. •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 thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 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): The oral clearance of thalidomide is 10.50 ± 2.10 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 LD 50 in rats is 113 mg/kg and 2 g/kg in mouse. Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA). Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test. Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA). There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Thalomid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Talidomida Thalidomide Thalidomidum •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): Thalidomide is a medication used to treat cancers, particularly newly diagnosed multiple myeloma, and erythema nodosum leprosum. 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 Theophylline interact?

•Drug A: Adalimumab •Drug B: Theophylline •Severity: MODERATE •Description: The serum concentration of Theophylline 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): For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis. •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): Theophylline, an xanthine derivative chemically similar to caffeine and theobromine, is used to treat asthma and bronchospasm. Theophylline has two distinct actions in the airways of patients with reversible (asthmatic) obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic 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): Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. •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): Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. •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): 0.3 to 0.7 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 40%, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. •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): 8 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): 0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days] 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days] 1.7 mL/kg/min [Children 1-4 years] 1.6 mL/kg/min [Children 4-12 years] 0.9 mL/kg/min [Children 13-15 years] 1.4 mL/kg/min [Children 16-17 years] 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease cirrhosis] 0.35 mL/kg/min [acute hepatitis] 0.65 mL/kg/min [cholestasis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid] •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, arrhythmias, and GI effects. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Elixophyllin, Elixophylline, Pulmophylline, Quibron-T, Theo-24, Theolair, Uniphyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teofilina Theophyllin •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): Theophylline is a xanthine used to manage the symptoms of asthma, COPD, and other lung conditions caused by reversible airflow obstruction.

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 Theophylline interact? Information: •Drug A: Adalimumab •Drug B: Theophylline •Severity: MODERATE •Description: The serum concentration of Theophylline 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): For the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, such as emphysema and chronic bronchitis. •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): Theophylline, an xanthine derivative chemically similar to caffeine and theobromine, is used to treat asthma and bronchospasm. Theophylline has two distinct actions in the airways of patients with reversible (asthmatic) obstruction; smooth muscle relaxation (i.e., bronchodilation) and suppression of the response of the airways to stimuli (i.e., non-bronchodilator prophylactic 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): Theophylline relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels and reduces airway responsiveness to histamine, methacholine, adenosine, and allergen. Theophylline competitively inhibits type III and type IV phosphodiesterase (PDE), the enzyme responsible for breaking down cyclic AMP in smooth muscle cells, possibly resulting in bronchodilation. Theophylline also binds to the adenosine A2B receptor and blocks adenosine mediated bronchoconstriction. In inflammatory states, theophylline activates histone deacetylase to prevent transcription of inflammatory genes that require the acetylation of histones for transcription to begin. •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): Theophylline is rapidly and completely absorbed after oral administration in solution or immediate-release solid oral dosage form. •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): 0.3 to 0.7 L/kg •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 40%, primarily to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. Biotransformation takes place through demethylation to 1-methylxanthine and 3-methylxanthine and hydroxylation to 1,3-dimethyluric acid. 1-methylxanthine is further hydroxylated, by xanthine oxidase, to 1-methyluric acid. About 6% of a theophylline dose is N-methylated to caffeine. Caffeine and 3-methylxanthine are the only theophylline metabolites with pharmacologic activity. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Theophylline does not undergo any appreciable pre-systemic elimination, distributes freely into fat-free tissues and is extensively metabolized in the liver. Renal excretion of unchanged theophylline in neonates amounts to about 50% of the dose, compared to about 10% in children older than three months and in adults. •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): 8 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): 0.29 mL/kg/min [Premature neonates, postnatal age 3-15 days] 0.64 mL/kg/min [Premature neonates, postnatal age 25-57 days] 1.7 mL/kg/min [Children 1-4 years] 1.6 mL/kg/min [Children 4-12 years] 0.9 mL/kg/min [Children 13-15 years] 1.4 mL/kg/min [Children 16-17 years] 0.65 mL/kg/min [Adults (16-60 years), otherwise healthy non-smoking asthmatics] 0.41 mL/kg/min [Elderly (>60 years), non-smokers with normal cardiac, liver, and renal function] 0.33 mL/kg/min [Acute pulmonary edema] 0.54 mL/kg/min [COPD >60 years, stable, non-smoker >1 year] 0.48 mL/kg/min [COPD with cor pulmonale] 1.25 mL/kg/min [Cystic fibrosis (14-28 years)] 0.31 mL/kg/min [Liver disease cirrhosis] 0.35 mL/kg/min [acute hepatitis] 0.65 mL/kg/min [cholestasis] 0.47 mL/kg/min [Sepsis with multi-organ failure] 0.38 mL/kg/min [hypothyroid] 0.8 mL/kg/min [hyperthyroid] •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, arrhythmias, and GI effects. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Elixophyllin, Elixophylline, Pulmophylline, Quibron-T, Theo-24, Theolair, Uniphyl •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teofilina Theophyllin •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): Theophylline is a xanthine used to manage the symptoms of asthma, COPD, and other lung conditions caused by reversible airflow obstruction. 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 Thiopental interact?

•Drug A: Adalimumab •Drug B: Thiopental •Severity: MAJOR •Description: The metabolism of Thiopental 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 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 as the sole anesthetic agent for brief (15 minute) procedures, for induction of anesthesia prior to administration of other anesthetic agents, to supplement regional anesthesia, to provide hypnosis during balanced anesthesia with other agents for analgesia or muscle relaxation, for the control of convulsive states during or following inhalation anesthesia or local anesthesia, in neurosurgical patients with increased intracranial pressure, and for narcoanalysis and narcosynthesis in psychiatric 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): Thiopental, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate Pentothal in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia •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): Thiopental binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •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. •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): Approximately 80% of the drug in the blood is bound to plasma protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, pentobarbital, that exists in concentrations approximately 3-10% that of the parent concentration. Thiopental and pentobarbital are also subject to both oxidation and hydroxylation to carboxylic acids and alcohols, respectively, all of which are pharmacologically inert. While many of the specifics regarding thiopental biotransformation have not been elucidated, including the enzymes responsible, the oxidation of thiopental to its carboxylic acid may be the major driver of thiopental detoxification as this product appears to account for 10-25% of renally excreted drug. •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): 3-8 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 may occur from rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure even to shock levels. Apnea, occasional laryngospasm, coughing and other respiratory difficulties with excessive or too rapid injections may occur. Lethal blood levels may be as low as 1 mg/100 mL for short-acting barbiturates; less if other depressant drugs or alcohol are also present. •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): Penthiobarbital Pentothiobarbital Thiopental Thiopentobarbital Thiopentobarbitone Thiopentobarbituric acid Thiopentone Tiopentale •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): Thiopental is a barbiturate used to induce general anesthesia, treat convulsions, and reduce intracranial pressure.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Thiopental interact? Information: •Drug A: Adalimumab •Drug B: Thiopental •Severity: MAJOR •Description: The metabolism of Thiopental 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 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 as the sole anesthetic agent for brief (15 minute) procedures, for induction of anesthesia prior to administration of other anesthetic agents, to supplement regional anesthesia, to provide hypnosis during balanced anesthesia with other agents for analgesia or muscle relaxation, for the control of convulsive states during or following inhalation anesthesia or local anesthesia, in neurosurgical patients with increased intracranial pressure, and for narcoanalysis and narcosynthesis in psychiatric 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): Thiopental, a barbiturate, is used for the induction of anesthesia prior to the use of other general anesthetic agents and for induction of anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli. Thiopental is an ultrashort-acting depressant of the central nervous system which induces hypnosis and anesthesia, but not analgesia. It produces hypnosis within 30 to 40 seconds of intravenous injection. Recovery after a small dose is rapid, with some somnolence and retrograde amnesia. Repeated intravenous doses lead to prolonged anesthesia because fatty tissues act as a reservoir; they accumulate Pentothal in concentrations 6 to 12 times greater than the plasma concentration, and then release the drug slowly to cause prolonged anesthesia •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): Thiopental binds at a distinct binding site associated with a Cl ionopore at the GABA A receptor, increasing the duration of time for which the Cl ionopore is open. The post-synaptic inhibitory effect of GABA in the thalamus is, therefore, prolonged. •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. •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): Approximately 80% of the drug in the blood is bound to plasma protein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Thiopental is extensively metabolized, primarily in the liver, resulting in only 0.3% of an administered dose being excreted unchanged in the urine. Ring desulfuration leads to the generation of an active metabolite, pentobarbital, that exists in concentrations approximately 3-10% that of the parent concentration. Thiopental and pentobarbital are also subject to both oxidation and hydroxylation to carboxylic acids and alcohols, respectively, all of which are pharmacologically inert. While many of the specifics regarding thiopental biotransformation have not been elucidated, including the enzymes responsible, the oxidation of thiopental to its carboxylic acid may be the major driver of thiopental detoxification as this product appears to account for 10-25% of renally excreted drug. •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): 3-8 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 may occur from rapid or repeated injections. Too rapid injection may be followed by an alarming fall in blood pressure even to shock levels. Apnea, occasional laryngospasm, coughing and other respiratory difficulties with excessive or too rapid injections may occur. Lethal blood levels may be as low as 1 mg/100 mL for short-acting barbiturates; less if other depressant drugs or alcohol are also present. •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): Penthiobarbital Pentothiobarbital Thiopental Thiopentobarbital Thiopentobarbitone Thiopentobarbituric acid Thiopentone Tiopentale •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): Thiopental is a barbiturate used to induce general anesthesia, treat convulsions, and reduce intracranial pressure. 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Thioridazine interact?

•Drug A: Adalimumab •Drug B: Thioridazine •Severity: MODERATE •Description: The metabolism of Thioridazine 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): For the treatment of schizophrenia and generalized anxiety disorder. •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): Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •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): Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •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): 60% •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% •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): 21-25 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): 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 =956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock •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): Thioridazin Thioridazine Thioridazinum Tioridazina •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): Thioridazine is a phenothiazine antipsychotic used to treat schizophrenia and generalized anxiety 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 CYP2C19 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Thioridazine interact? Information: •Drug A: Adalimumab •Drug B: Thioridazine •Severity: MODERATE •Description: The metabolism of Thioridazine 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): For the treatment of schizophrenia and generalized anxiety disorder. •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): Thioridazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Thioridazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •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): Thioridazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; blocks alpha-adrenergic effect, depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •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): 60% •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% •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): 21-25 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): 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 =956-1034 mg/kg (Orally in rats); Agitation, blurred vision, coma, confusion, constipation, difficulty breathing, dilated or constricted pupils, diminished flow of urine, dry mouth, dry skin, excessively high or low body temperature, extremely low blood pressure, fluid in the lungs, heart abnormalities, inability to urinate, intestinal blockage, nasal congestion, restlessness, sedation, seizures, shock •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): Thioridazin Thioridazine Thioridazinum Tioridazina •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): Thioridazine is a phenothiazine antipsychotic used to treat schizophrenia and generalized anxiety 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 CYP2C19 substrates. The severity of the interaction is moderate.

Does Adalimumab and Thiotepa interact?

•Drug A: Adalimumab •Drug B: Thiotepa •Severity: MAJOR •Description: The metabolism of Thiotepa 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): ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric 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): The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases 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. These drugs act nonspecifically. •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 alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases 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. These drugs act nonspecifically. •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): Urinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. •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 to 4.1 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): 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals] •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): Tepadina •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): Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Thiotepa interact? Information: •Drug A: Adalimumab •Drug B: Thiotepa •Severity: MAJOR •Description: The metabolism of Thiotepa 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): ThioTEPA is used a as conditioning treatment prior to allogeneic or autologous haematopoietic progenitor cell transplantation (HPCT) in haematological diseases in adult and paediatric patients. Also, when high dose chemotherapy with HPCT support it is appropriate for the treatment of solid tumours in adult and paediatric 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): The unstable nitrogen-carbon groups alkylate with DNA causing irrepairable DNA damage. They stop tumor growth by crosslinking guanine nucleobases 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. These drugs act nonspecifically. •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 alkyl group is attached to the guanine base of DNA, at the number 7 nitrogen atom of the imidazole ring. They stop tumor growth by crosslinking guanine nucleobases 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. These drugs act nonspecifically. •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): Urinary excretion of 14C-labeled thiotepa and metabolites in a 34-year old patient with metastatic carcinoma of the cecum who received a dose of 0.3 mg/kg intravenously was 63%. •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 to 4.1 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): 446 +/- 63 mL/min [female patients (45 to 84 years) with advanced stage ovarian cancer receiving 60 mg and 80 mg thiotepa by intravenous infusion on subsequent courses given at 4-week intervals] •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): Tepadina •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): Thiotepa is an alkylating agent used to prevent graft rejection in stem cell transplantation and to treat a variety of malignancies including certain types of adenocarcinoma and superficial bladder carcinomas. 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 Thiothixene interact?

•Drug A: Adalimumab •Drug B: Thiothixene •Severity: MODERATE •Description: The metabolism of Thiothixene 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 management of schizophrenia. •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): Thiothixene is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. Although widely used in the treatment of schizophrenia for several decades, thiothixene is seldom used today in favor of atypical antipsychotics such as risperidone. •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): Thiothixene 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). •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): 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): 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): 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 central nervous system depression, coma, difficulty swallowing, dizziness, drowsiness, head tilted to the side, low blood pressure, muscle twitching, rigid muscles, salivation, tremors, walking disturbances, and weakness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Navane •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): Thiothixene is an antipsychotic indicated for the management of schizophrenia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Thiothixene interact? Information: •Drug A: Adalimumab •Drug B: Thiothixene •Severity: MODERATE •Description: The metabolism of Thiothixene 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 management of schizophrenia. •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): Thiothixene is an antipsychotic of the thioxanthene series. Navane possesses certain chemical and pharmacological similarities to the piperazine phenothiazines and differences from the aliphatic group of phenothiazines. Although widely used in the treatment of schizophrenia for several decades, thiothixene is seldom used today in favor of atypical antipsychotics such as risperidone. •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): Thiothixene 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). •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): 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): 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): 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 central nervous system depression, coma, difficulty swallowing, dizziness, drowsiness, head tilted to the side, low blood pressure, muscle twitching, rigid muscles, salivation, tremors, walking disturbances, and weakness. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Navane •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): Thiothixene is an antipsychotic indicated for the management of schizophrenia. 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 Tibolone interact?

•Drug A: Adalimumab •Drug B: Tibolone •Severity: MINOR •Description: Tibolone may increase the thrombogenic activities of Adalimumab. •Extended Description: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. •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 post-menopausal symptoms and for the prevention of 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): Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator. Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety. •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): This drug's effects are owed to the activity of its metabolites in various tissues. Upon ingestion, tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body. The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens. In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner. Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences. The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process. In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway. The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2. •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): Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug. •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): Tibolone is 96% bound to plasma proteins, most likely albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites 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-life is approximately 45 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): Elimination of tibolone is not dependent renal function. •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): >2000 mg/kg The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations. Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage. Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine. •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): tibolona Tibolone tibolonum •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

Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. The severity of the interaction is minor.

Question: Does Adalimumab and Tibolone interact? Information: •Drug A: Adalimumab •Drug B: Tibolone •Severity: MINOR •Description: Tibolone may increase the thrombogenic activities of Adalimumab. •Extended Description: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. •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 post-menopausal symptoms and for the prevention of 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): Tibolone prevents bone loss and treating post-menopausal symptoms without stimulating the endometrial tissues, which may lead to malignancy. Typical, drugs that treat post-menopausal symptoms such as estrogen, have a proliferative effect on the endometrium, increasing the risk of endometrial carcinoma. The effects on the bone, brain and vaginal tissues can be explained by the estrogenic activity of tibolone. It is important to note that activity is not expressed in the endometrium. Tibolone behaves differently from estrogen plus progesterone combinations on the breast. Therefore, tibolone can be characterized as a selective estrogen activity regulator. Tibolone has been demonstrated to be an effective agent in treating symptoms associated with menopause. A 16 week trial in 1189 women examined the effect of tibolone 2.5 mg once daily on climacteric symptoms. Women treated with tibolone showed improvement from baseline in typical menopausal symptoms including hot flashes, sweating, insomnia, and anxiety. •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): This drug's effects are owed to the activity of its metabolites in various tissues. Upon ingestion, tibolone is quickly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The specific tissue-selective effects of tibolone occur due to the metabolism, regulation of enzymes and receptor activation that varies in different tissues of the body. The bone-conserving effects occur due to estradiol receptor activation, while the progesterone and androgen receptors are not involved in this process. Breast tissue of monkeys is not found to be stimulated after tibolone administration, as occurs with estrogen plus progesterone used in combination. This is explained by the fact that tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II. The combined effects of this process prevent the conversion to active estrogens. In the uterus, the progestogenic activity of the Delta(4)-metabolite and the effect on estrogen-inactivating enzymes prevent estrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone has been shown to regulate estrogenic activity in several tissue types by influencing the availability of estrogenic compounds for the estradiol receptor in a selective manner. Additionally, tibolone modulates cellular homeostasis in the breast by preventing breast tissue proliferation and stimulating cell apoptosis. Tibolone does not stimulate the endometrium because of the action of its highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulfatase (inhibition)-sulfotransferase (stimulation) system. The estrogenic metabolites of tibolone have direct, favorable effects on the cardiovascular system and, in animal models, this drug has shown no adverse consequences. The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone-preserving effects of tibolone are the result of estradiol receptor activation, while other steroid receptors, mainly the progesterone and androgen receptors, are not involved in this process. In a study of monkeys, breast tissue was not stimulated, which occurs with estrogen and progesterone, because tibolone and its metabolites inhibit sulfatase and 17 beta-hydroxysteroid _dehydrogenase (HSD) type I and stimulate _sulfotransferase and 17 beta-HSD type II. The simultaneous effects of this process halt conversion to active estrogens. Additionally, tibolone affects cellular homeostasis in the breast by preventing proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium due to the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) pathway. The levels of tibolone metabolites and the alteration of hormonal activities vary according to the tissue type. In endometrial tissue the Δ4-isomer functions as a progestagen, however, in the brain and liver, it shows androgenic effects. In breast tissue, the primary actions of tibolone are strong inhibition of sulfatase activity and weak inhibition of 17β-hydroxysteroid dehydrogenase activity, which leads to blocking the conversion estrone sulfate to E2. •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): Tibolone is extensively and rapidly absorbed after oral administration. The parent drug undergoes extensive metabolism, with. Greater than 80% of a radioactive dose excreted from the body as metabolites, which suggests very low plasma concentrations of tibolone. Plasma concentrations of the metabolites appear within 30 minutes and peak within 1–1.5 hours.2,7 The plasma concentrations of the hydroxymetabolites are higher than those of the ∆4-isomer. Food does not appear to have an effect on the absorption of this drug. •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): Tibolone is 96% bound to plasma proteins, most likely albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tibolone is metabolized mainly in the liver. The cytochrome P450 isoenzyme system is involved in minor hydroxylation of tibolone. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has both progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulfated form. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Excreted in the urine and feces in the form of sulfated metabolites. About 40% of the drug is excreted as metabolites in urine. The predominant route of elimination of tibolone is via the feces: about 60% of the drug is excreted as metabolites 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-life is approximately 45 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): Elimination of tibolone is not dependent renal function. •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): >2000 mg/kg The Million Women Study (MWS), which had a prospective observational design, studied the use of hormone replacement therapy. The results indicated that the increase in the incidence of breast cancer with estrogen and progestogen (compared to estrogen alone) was greater than the reduction in occurrence of endometrial cancer associated with adding progestogen to estrogen therapy. The MWS also reported a marked increase in the incidence of breast cancer with tibolone and with implanted and transdermal estrogen-only preparations. Tibolone treatment in rodent studies showed an increased association with the development of a range of tumors in long-term oral carcinogenicity studies. These tumors included pituitary adenomas, mammary carcinomas and fibroadenomas, hepatic adenomas, uterine carcinoma, stromal polyps and stromal sarcoma, and carcinomas of the urinary bladder and testes. Tibolone failed to show any evidence of genotoxicity in studies for gene mutations, chromosomal damage as well as DNA damage. Other adverse effects these include dizziness, headache, nausea, abdominal pain, rashes, pruritus, weight gain, edema, and migraine. •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): tibolona Tibolone tibolonum •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: Therapeutic immune globulins have been associated with the risk for adverse thromboembolic events, oftentimes leading to withdrawal from therapy. The use of estrogen-containing preparations, such as oral contraceptives (OC), is also a well established risk factor for venous thrombosis. Co-administration of two agents may further elevate the risk for developing thrombotic disorders. The severity of the interaction is minor.

Does Adalimumab and Ticagrelor interact?

•Drug A: Adalimumab •Drug B: Ticagrelor •Severity: MODERATE •Description: The metabolism of Ticagrelor 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): Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery 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): Ticagrelor is a P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias. •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): Ticagrelor is a P2Y 12 receptor antagonist. The P2Y 12 receptor couples with Gα i2 and other G i proteins which inhibit adenylyl cyclase. G i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y 12 receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke. •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): Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*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 steady state volume of distribution of ticagrelor is 88 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly 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): Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 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): The renal clearance of ticagrelor is 0.00584L/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 may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Brilinta, Brilique •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ticagrelor •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): Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke and cardiovascular death.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Ticagrelor interact? Information: •Drug A: Adalimumab •Drug B: Ticagrelor •Severity: MODERATE •Description: The metabolism of Ticagrelor 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): Ticagrelor is indicated to reduce the risk of cardiovascular death, myocardial infarction, and stroke in patients with acute coronary syndrome or a history of myocardial infarction. Ticagrelor is also indicated to reduce the risk of a first myocardial infarction or stroke in high risk patients with coronary artery 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): Ticagrelor is a P2Y 12 receptor antagonist that inhibits the formation of thromboses to reduce the risk of myocardial infarction and ischemic stroke. It has a moderate duration of action as it is given twice daily, and a wide therapeutic index as high single doses are well tolerated. Patients should be counselled regarding the risk of bleeding, dyspnea, and bradyarrhythmias. •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): Ticagrelor is a P2Y 12 receptor antagonist. The P2Y 12 receptor couples with Gα i2 and other G i proteins which inhibit adenylyl cyclase. G i mediated signalling also activates PI3K, Akt, Rap1b, and potassium channels. The downstream effects of these activities mediate hemostasis and lead to platelet aggregation. Antagonism of the P2Y 12 receptor reduces development of occlusive thromboses, which can reduce the risk of myocardial infarction and ischemic stroke. •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): Ticagrelor is 36% orally bioavailable. A single 200mg oral dose of ticagrelor reaches a C max of 923ng/mL, with a T max of 1.5 hours and an AUC of 6675ng*h/mL. The active metabolite of ticagrelor reaches a C max of 264ng/mL, with a T max of 3.0 hours and an AUC of 2538ng*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 steady state volume of distribution of ticagrelor is 88 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Ticagrelor and its active metabolite ate >99% protein bound in plasma, particularly albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The complete structure of all ticagrelor metabolites are not well defined. Ticagrelor can be dealkylated at postition 5 of the cyclopentane ring to form the active AR-C124910XX. AR-C124910XX's cyclopentane ring can be further glucuronidated or the alkyl chain attached to the sulfur can be hydroxylated. Ticagrelor can also be glucuronidated or hydroxylated. Ticagrelor can also be N-dealkylated to form AR-C133913XX, which is further glucuronidated or hydroxylated. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): A radiolabelled dose of ticagrelor is 57.8% recovered in feces and 26.5% recovered in urine. Less than 1% of the dose is recovered as the unmetabolized parent drug. The active metabolite AC-C124910XX makes up 21.7% of the recovery in the feces. The metabolite AR-C133913XX makes up 9.2% of the recovery in the urine and 2.7% of the recovery in the feces. Other minor metabolites are predominantly 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): Ticagrelor has a plasma half life of approximately 8 hours, while the active metabolite has a plasma half life of approximately 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): The renal clearance of ticagrelor is 0.00584L/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 may present with bleeding, nausea, vomiting, diarrhea, and ventricular pauses. Overdose can be managed through symptomatic and supportive treatment, including ECG monitoring. Dialysis is not expected to remove ticagrelor from the blood due to it being highly protein bound. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Brilinta, Brilique •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Ticagrelor •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): Ticagrelor is a P2Y12 platelet inhibitor used in patients with a history of myocardial infarction or with acute coronary syndrome (ACS) to prevent future myocardial infarction, stroke and cardiovascular death. 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 Tick-borne encephalitis vaccine (whole virus, inactivated) interact?

•Drug A: Adalimumab •Drug B: Tick-borne encephalitis vaccine (whole virus, inactivated) •Severity: MODERATE •Description: The therapeutic efficacy of Tick-borne encephalitis vaccine (whole virus, 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 Tick-borne encephalitis vaccine (whole virus, inactivated) interact? Information: •Drug A: Adalimumab •Drug B: Tick-borne encephalitis vaccine (whole virus, inactivated) •Severity: MODERATE •Description: The therapeutic efficacy of Tick-borne encephalitis vaccine (whole virus, 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 Ticlopidine interact?

•Drug A: Adalimumab •Drug B: Ticlopidine •Severity: MODERATE •Description: The metabolism of Ticlopidine 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): Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke. •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): Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo. •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 active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine. •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 is greater than 80%. Food increases absorption by approximately 20%. •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 was not quantified. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%). •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 following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age. •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): Ticlopidine clearance was not quantified, but clearance decreases with age. •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): Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine. •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): Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Ticlopidine interact? Information: •Drug A: Adalimumab •Drug B: Ticlopidine •Severity: MODERATE •Description: The metabolism of Ticlopidine 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): Used in patients, who have had a stroke or stroke precursors and who cannot take aspirin or aspirin has not worked, to try to prevent another thrombotic stroke. •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): Ticlopidine is a prodrug that is metabolised to an as yet undetermined metabolite that acts as a platelet aggregation inhibitor. Inhibition of platelet aggregation causes a prolongation of bleeding time. In its prodrug form, ticlopidine has no significant in vitro activity at the concentrations attained in vivo. •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 active metabolite of ticlopidine prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of ticlopidine. •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 is greater than 80%. Food increases absorption by approximately 20%. •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 was not quantified. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein (about 15% or less). •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Ticlopidine is metabolized extensively by the liver with only trace amounts of intact drug detected. At least 20 metabolites have been identified. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Ticlopidine is eliminated mostly in the urine (60%) and somewhat in the feces (23%). •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 following a single 250-mg dose is approximately 7.9 hours in subjects 20 to 43 years of age and 12.6 hours in subjects 65 to 76 years of age. With repeated dosing (250 mg twice a day), half-life is about 4 days in subjects 20 to 43 years of age and about 5 days in subjects 65 to 76 years of age. •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): Ticlopidine clearance was not quantified, but clearance decreases with age. •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): Single oral doses of ticlopidine at 1600 mg/kg and 500 mg/kg were lethal to rats and mice, respectively. Symptoms of acute toxicity were GI hemorrhage, convulsions, hypothermia, dyspnea, loss of equilibrium and abnormal gait. The FDA label includes a black-box warning of neutropenia, aplastic anemia, thrombotic thrombocytopenia purpura, and agranulocytosis, so it is necessary to monitor patients' WBC and platelets when they are taking ticlopidine. •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): Ticlopidine is a platelet aggregation inhibitor used in the prevention of conditions associated with thrombi, such as stroke and transient ischemic attacks (TIA). 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 Tildrakizumab interact?

•Drug A: Adalimumab •Drug B: Tildrakizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tildrakizumab. •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): Moderate-severe plaque psoriasis,. •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): Tildrakuzimab is a targeted immunomodulator that decreases inflammation by inhibiting the action of various cytokines associated with plaque psoriasis, thus relieving its symptom of scaly plaques,. •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): This drug selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function IL-23 regulates Th17 cells and is a powerful activator of keratinocyte proliferation. Targeting IL-23p19 alone has been found to be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis. Upon administration, downregulation of Th17 and Th22 cell responses occur. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines. •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 (± SD) steady-state trough concentrations at 16 weeks post initiation of treatment ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%). The absolute bioavailability of tildrakizumab is estimated to be about 73-80% after subcutaneous administration. The peak concentration (Cmax) is reached by approximately 6 days. •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 (CV%) volume of distribution is 10.8 L (24%). •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): The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed. •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 half-life is approximately 23 days (23%). •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 mean (CV%) systemic clearance is 0.32 L/day (38%). •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): It is advised to evaluate patients for tuberculosis infection prior to initiating treatment with ILUMYA. This drug may increase the risk of infection. It is advisable to perform tests for current tuberculosis status, as this drug may lead to reactivation of latent infection. A common issue for monoclonal antibody drugs is the development of antibodies to the drugs, thus rendering them less effective or completely ineffective. A clinical trial was done to assess antibody development to this drug,. Up until week 64, approximately 6.5% of subjects treated with ILUMYA 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all patients receiving ILUMYA) had antibodies that were considered neutralizing. The development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and decreased efficacy. Most common (≥ 1% and at a higher rate than placebo) adverse reactions associated with ILUMYA treatment are upper respiratory infections, injection site reactions, and diarrhea. Cases of angioedema and urticaria occurred in ILUMYA treated subjects in various clinical trials. If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy should be initiated. In an embryo-fetal study, subcutaneous doses up to 300 mg/kg tildrakizumab were given to pregnant cynomolgus monkeys once every two weeks during organogenesis to 118 days gestation (22 days from parturition). No maternal or embryo-fetal toxicities were seen at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ilumya •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): Tildrakizumab is an interleukin-23 antagonist used to treat moderate to severe plaque psoriasis.

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 Tildrakizumab interact? Information: •Drug A: Adalimumab •Drug B: Tildrakizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tildrakizumab. •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): Moderate-severe plaque psoriasis,. •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): Tildrakuzimab is a targeted immunomodulator that decreases inflammation by inhibiting the action of various cytokines associated with plaque psoriasis, thus relieving its symptom of scaly plaques,. •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): This drug selectively binds interleukin (IL)-23 p19 subunit of cytokine IL-23 and neutralizes its function IL-23 regulates Th17 cells and is a powerful activator of keratinocyte proliferation. Targeting IL-23p19 alone has been found to be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis. Upon administration, downregulation of Th17 and Th22 cell responses occur. IL-23 is a naturally occurring cytokine that is involved in inflammatory and immune responses. Tildrakizumab inhibits the release of proinflammatory cytokines and chemokines. •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 (± SD) steady-state trough concentrations at 16 weeks post initiation of treatment ranged from 1.22 ± 0.94 mcg/mL to 1.47 ± 1.12 mcg/mL. The geometric mean (CV%) steady-state Cmax was 8.1 mcg/mL (34%). The absolute bioavailability of tildrakizumab is estimated to be about 73-80% after subcutaneous administration. The peak concentration (Cmax) is reached by approximately 6 days. •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 (CV%) volume of distribution is 10.8 L (24%). •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): The metabolic pathway of tildrakizumab has not been characterized. As a humanized IgG1/k monoclonal antibody, tildrakizumab is expected to be degraded into small peptides and amino acids via catabolic pathways in a manner similar to endogenous IgG. The AUCinf of dextromethorphan (CYP2D6 substrate) increased by 20% when used concomitantly with tildrakizumab 200 mg (two times the approved recommended dose) administered subcutaneously at Weeks 0 and 4 in subjects with plaque psoriasis. No clinically significant changes in AUCinf of caffeine (CYP1A2 substrate), warfarin (CYP2C9 substrate), omeprazole (CYP2C19 substrate), and midazolam (CYP3A4 substrate) were observed. •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 half-life is approximately 23 days (23%). •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 mean (CV%) systemic clearance is 0.32 L/day (38%). •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): It is advised to evaluate patients for tuberculosis infection prior to initiating treatment with ILUMYA. This drug may increase the risk of infection. It is advisable to perform tests for current tuberculosis status, as this drug may lead to reactivation of latent infection. A common issue for monoclonal antibody drugs is the development of antibodies to the drugs, thus rendering them less effective or completely ineffective. A clinical trial was done to assess antibody development to this drug,. Up until week 64, approximately 6.5% of subjects treated with ILUMYA 100 mg developed antibodies to tildrakizumab. Of the subjects who developed antibodies to tildrakizumab, approximately 40% (2.5% of all patients receiving ILUMYA) had antibodies that were considered neutralizing. The development of neutralizing antibodies to tildrakizumab was associated with lower serum tildrakizumab concentrations and decreased efficacy. Most common (≥ 1% and at a higher rate than placebo) adverse reactions associated with ILUMYA treatment are upper respiratory infections, injection site reactions, and diarrhea. Cases of angioedema and urticaria occurred in ILUMYA treated subjects in various clinical trials. If a hypersensitivity reaction occurs, the drug should be discontinued immediately and appropriate therapy should be initiated. In an embryo-fetal study, subcutaneous doses up to 300 mg/kg tildrakizumab were given to pregnant cynomolgus monkeys once every two weeks during organogenesis to 118 days gestation (22 days from parturition). No maternal or embryo-fetal toxicities were seen at doses up to 300 mg/kg (159 times the MRHD of 100 mg, based on AUC comparison). Tildrakizumab crossed the placenta in monkeys. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ilumya •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): Tildrakizumab is an interleukin-23 antagonist used to treat moderate to severe plaque psoriasis. 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 Timolol interact?

•Drug A: Adalimumab •Drug B: Timolol •Severity: MODERATE •Description: The metabolism of Timolol 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): Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure. In certain cases, timolol is used in the prevention of migraine headaches. •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): Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses. •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): Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis. •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 systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5%, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers. The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop 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): 1.3 - 1.7 L/kg Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of timolol is not extensive and is estimated to be about 10%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Timolol and its metabolites are mainly found 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): Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of 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): One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers. •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 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse. Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Azarga, Betimol, Combigan, Cosopt, Duotrav, Istalol, Timoptic, Xalacom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Timolol Timololo Timololum •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): Timolol is a non-selective beta adrenergic blocker used in the treatment of elevated intraocular pressure in ocular hypertension or open angle glaucoma.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Timolol interact? Information: •Drug A: Adalimumab •Drug B: Timolol •Severity: MODERATE •Description: The metabolism of Timolol 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): Ophthalmic timolol is indicated for the treatment of increased intraocular pressure in patients with ocular hypertension or open-angle glaucoma. The oral form of this drug is used to treat high blood pressure. In certain cases, timolol is used in the prevention of migraine headaches. •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): Timolol, when administered by the ophthalmic route, rapidly reduces intraocular pressure. When administered in the tablet form, it reduces blood pressure, heart rate, and cardiac output, and decreases sympathetic activity.. This drug has a fast onset of action, usually occurring within 20 minutes of the administration of an ophthalmic dose. Timolol maleate can exert pharmacological actions for as long as 24 hours if given in the 0.5% or 0.25% doses. •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): Timolol competes with adrenergic neurotransmitters for binding to beta(1)-adrenergic receptors in the heart and the beta(2)-receptors in the vascular and bronchial smooth muscle. This leads to diminished actions of catecholamines, which normally bind to adrenergic receptors and exert sympathetic effects leading to an increase in blood pressure and heart rate. Beta(1)-receptor blockade by timolol leads to a decrease in both heart rate and cardiac output during rest and exercise, and a decrease in both systolic and diastolic blood pressure. In addition to this, a reduction in reflex orthostatic hypotension may also occur. The blockade of beta(2) receptors by timolol in the blood vessels leads to a decrease in peripheral vascular resistance, reducing blood pressure. The exact mechanism by which timolol reduces ocular pressure is unknown at this time, however, it likely decreases the secretion of aqueous humor in the eye. According to one study, the reduction of aqueous humor secretion may occur through the decreased blood supply to the ciliary body resulting from interference with the active transport system or interference with prostaglandin biosynthesis. •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 systemic bioavailability of the ophthalmic eyedrop in one study of healthy volunteers was 78.0 ± 24.5%, indicating that caution must be observed when this drug is administered, as it may be significantly absorbed and have various systemic effects. Another study measured the bioavailability of timolol eyedrops to be 60% in healthy volunteers. The peak concentration of ophthalmic timolol in plasma, Cmax was about 1.14 ng/ml in most subjects within 15 minutes following the administration of timolol by the ophthalmic route. The mean area under the curve (AUC) was about 6.46 ng/ml per hour after intravenous injection and about 4.78 ng/ml per hour following eyedrop 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): 1.3 - 1.7 L/kg Timolol is distributed to the following tissues: the conjunctiva, cornea, iris, sclera, aqueous humor, kidney, liver, and lung. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of timolol is not extensive and is estimated to be about 10%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Timolol is metabolized in the liver by the cytochrome P450 2D6 enzyme, with minor contributions from CYP2C19. 15-20% of a dose undergoes first-pass metabolism. Despite its relatively low first pass metabolism, timolol is 90% metabolized. Four metabolites of timolol have been identified, with a hydroxy metabolite being the most predominant. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Timolol and its metabolites are mainly found 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): Timolol half-life was measured at 2.9 ± 0.3 h hours in a clinical study of 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): One pharmacokinetic study in healthy volunteers measured the total plasma clearance of timolol to be 557 ± 61 ml/min. Another study determined the total clearance 751.5 ± 90.6 ml/min and renal clearance to be 97.2 ± 10.1 ml/min in healthy volunteers. •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 for timolol maleate is 1028 mg/kg in the rat and 1137 mg/kg in the mouse. Symptoms of timolol overdose may include dizziness, headache, shortness of breath, bradycardia, in addition to bronchospasm. Sometimes, an overdose may lead to cardiac arrest. An overdose of timolol can be reversed with dialysis, however, patients with renal failure may not respond as well to dialysis treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Azarga, Betimol, Combigan, Cosopt, Duotrav, Istalol, Timoptic, Xalacom •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Timolol Timololo Timololum •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): Timolol is a non-selective beta adrenergic blocker used in the treatment of elevated intraocular pressure in ocular hypertension or open angle glaucoma. 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 Tioguanine interact?

•Drug A: Adalimumab •Drug B: Tioguanine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tioguanine. •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 and remission consolidation treatment of acute nonlymphocytic leukemias. •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): Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic 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. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). •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): Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides. •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 incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%) •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. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. •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): When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 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): Oral, mouse: LD 50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lanvis, Tabloid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Amino 6MP 6-Mercaptoguanine 6-TG 6-Thioguanine Thioguanine Tioguanin Tioguanina Tioguanine Tioguaninum •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): Tioguanine is a purine analogue antineoplastic agent used for the induction of remission, and for remission consolidation in patients with acute nonlymphocytic anemias.

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 Tioguanine interact? Information: •Drug A: Adalimumab •Drug B: Tioguanine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tioguanine. •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 and remission consolidation treatment of acute nonlymphocytic leukemias. •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): Thioguanine is an antineoplastic anti-metabolite used in the treatment of several forms of leukemia including acute nonlymphocytic 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. Thioguanine was first synthesized and entered into clinical trial more than 30 years ago. It is a 6-thiopurine analogue of the naturally occurring purine bases hypoxanthine and guanine. Intracellular activation results in incorporation into DNA as a false purine base. An additional cytotoxic effect is related to its incorporation into RNA. Thioguanine is cross-resistant with mercaptopurine. Cytotoxicity is cell cycle phase-specific (S-phase). •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): Thioguanine competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) and is itself converted to 6-thioguanilyic acid (TGMP), which reaches high intracellular concentrations at therapeutic doses. TGMP interferes with the synthesis of guanine nucleotides by its inhibition of purine biosynthesis by pseudofeedback inhibition of glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway of purine ribonucleotide synthesis. TGMP also inhibits the conversion of inosinic acid (IMP) to xanthylic acid (XMP) by competition for the enzyme IMP dehydrogenase. Thioguanine nucleotides are incorporated into both the DNA and the RNA by phosphodiester linkages, and some studies have shown that incorporation of such false bases contributes to the cytotoxicity of thioguanine. Its tumor inhibitory properties may be due to one or more of its effects on feedback inhibition of de novo purine synthesis; inhibition of purine nucleotide interconversions; or incorporation into the DNA and RNA. The overall result of its action is a sequential blockade of the utilization and synthesis of the purine nucleotides. •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 incomplete and variable, averaging approximately 30% of the administered dose (range: 14% to 46%) •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. First converted to 6-thioguanilyic acid (TGMP). TGMP is further converted to the di- and tri-phosphates, thioguanosine diphosphate (TGDP) and thioguanosine triphosphate (TGTP) by the same enzymes that metabolize guanine nucleotides. •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): When the compound was given in singles doses of 65 to 300 mg/m^2, the median plasma half-disappearance time was 80 minutes (range 25-240 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): Oral, mouse: LD 50 = 160 mg/kg. Symptoms of overdose include nausea, vomiting, malaise, hypotension, and diaphoresis. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lanvis, Tabloid •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): 2-Amino 6MP 6-Mercaptoguanine 6-TG 6-Thioguanine Thioguanine Tioguanin Tioguanina Tioguanine Tioguaninum •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): Tioguanine is a purine analogue antineoplastic agent used for the induction of remission, and for remission consolidation in patients with acute nonlymphocytic anemias. 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 Tiotropium interact?

•Drug A: Adalimumab •Drug B: Tiotropium •Severity: MODERATE •Description: The metabolism of Tiotropium 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): Tiotropium powder for inhalation is indicated for the maintenance of bronchospasm in COPD and to prevent exacerbations of COPD. A combination tiotropium and olodaterol metered inhalation spray is indicated for maintenance of COPD. A tiotropium inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 12 or more years old. A tiotropium metered inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 6 or more years old. •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): Tiotropium is a long acting antimuscarinic that causes bronchodilation. The effects of tiotropium last over 24 hours and there is a wide therapeutic index as overdoses are uncommon even at doses well above the recommended maximum. •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): Tiotropium is an antagonist of muscarinic receptors M 1 to M 5. Inhibition of the M 3 receptor in the smooth muscle of the lungs leads to relaxation of smooth muscle and bronchodilation. •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): 33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. A dry powder for inhalation is 19.5% bioavailable. Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 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): The volume of distribution of tiotropium is 32L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tiotropium is 72% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tiotropium is not heavily metabolized in the body. 74% of an intravenous dose is excreted in the urine as unchanged drug. Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. In vitro experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 74% of intravenous tiotropium was excreted unchanged in urine. 14% of a dry powder inhalation dose was excreted unchanged in the urine. 24 hour urinary excretion after 21 days of 5µg once daily inhalation in patients with COPD is 18.6% and in patients with asthma is 12.8%. •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 tiotropium is 24 hours in patients with COPD and 44 hours in patients with asthma. •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 clearance of tiotropium is 880mL/min in healthy subjects receiving 5µg daily. The renal clearance of tiotropium was 669mL/min. Patients <65 years old demonstrated a clearance of 365mL/min while patients ≥65 demonstrated a clearance of 271mL/min. This decreased clearance is not associated with increased AUC or C max. •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 altered mental status, tremors, abdominal pain, and severe constipation. However, doses of up to 282µg did not lead to systemic anticholinergic effects in a trial of 6 patients. In case of overdose, stop tiotropium and being symptomatic and supportive therapy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Inspiolto Respimat, Spiriva, Spiriva Respimat, Stiolto •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): Tiotropium is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tiotropium interact? Information: •Drug A: Adalimumab •Drug B: Tiotropium •Severity: MODERATE •Description: The metabolism of Tiotropium 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): Tiotropium powder for inhalation is indicated for the maintenance of bronchospasm in COPD and to prevent exacerbations of COPD. A combination tiotropium and olodaterol metered inhalation spray is indicated for maintenance of COPD. A tiotropium inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 12 or more years old. A tiotropium metered inhalation spray is indicated for the maintenance of bronchospasm in COPD, to prevent exacerbations of COPD, and to treat asthma in patients 6 or more years old. •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): Tiotropium is a long acting antimuscarinic that causes bronchodilation. The effects of tiotropium last over 24 hours and there is a wide therapeutic index as overdoses are uncommon even at doses well above the recommended maximum. •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): Tiotropium is an antagonist of muscarinic receptors M 1 to M 5. Inhibition of the M 3 receptor in the smooth muscle of the lungs leads to relaxation of smooth muscle and bronchodilation. •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): 33% of an inhaled solution reaches systemic circulation, while oral solutions have a bioavailability of 2-3%. A dry powder for inhalation is 19.5% bioavailable. Tiotropium metered spray for inhalation reaches a maximum concentration in 5-7 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): The volume of distribution of tiotropium is 32L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tiotropium is 72% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tiotropium is not heavily metabolized in the body. 74% of an intravenous dose is excreted in the urine as unchanged drug. Tiotropium is nonenzymatically cleaved to the inactive metabolites N-methylscopine and dithienylglycolic acid. In vitro experiments show cytochrome P-450 dependent oxidation and glutathione conjugation to further metabolites. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 74% of intravenous tiotropium was excreted unchanged in urine. 14% of a dry powder inhalation dose was excreted unchanged in the urine. 24 hour urinary excretion after 21 days of 5µg once daily inhalation in patients with COPD is 18.6% and in patients with asthma is 12.8%. •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 tiotropium is 24 hours in patients with COPD and 44 hours in patients with asthma. •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 clearance of tiotropium is 880mL/min in healthy subjects receiving 5µg daily. The renal clearance of tiotropium was 669mL/min. Patients <65 years old demonstrated a clearance of 365mL/min while patients ≥65 demonstrated a clearance of 271mL/min. This decreased clearance is not associated with increased AUC or C max. •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 altered mental status, tremors, abdominal pain, and severe constipation. However, doses of up to 282µg did not lead to systemic anticholinergic effects in a trial of 6 patients. In case of overdose, stop tiotropium and being symptomatic and supportive therapy. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Inspiolto Respimat, Spiriva, Spiriva Respimat, Stiolto •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): Tiotropium is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD). 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 Tipranavir interact?

•Drug A: Adalimumab •Drug B: Tipranavir •Severity: MODERATE •Description: The metabolism of Tipranavir 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 combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease 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): Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV 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): Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses. •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 is limited, although no absolute quantification of absorption is 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): Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. •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): 5-6 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): 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 LD 50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aptivus •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): Tipranavir is a protease inhibitor used to treat HIV-1 resistant to more than 1 protease inhibitor.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tipranavir interact? Information: •Drug A: Adalimumab •Drug B: Tipranavir •Severity: MODERATE •Description: The metabolism of Tipranavir 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 combination antiretroviral treatment of HIV-1 infected adult patients with evidence of viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease 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): Tipranavir is a non-peptidic protease inhibitor (PI) of HIV. Protease inhibitors block the part of HIV called protease. HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Nelfinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV 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): Tipranavir (TPV) is a non-peptidic HIV-1 protease inhibitor that inhibits the processing of the viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Two mechanisms are suggested in regards to the potency of tipranavir: 1. Tipravanir may bind to the active site of the protease enzyme with fewer hydrogen bonds than peptidic protease inhibitors, which results in increased flexibility, allowing it to fit into the active site of the enzyme in viruses that have become resistance to other protease inhibitors. This also enables tipranavir to adjust to amino acid substitutions at the active site. 2. Tipranavir's strong hydrogen bonding interaction with the amide backbone of the protease active site Asp30 may lead to its activity against resistant viruses. •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 is limited, although no absolute quantification of absorption is 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): Extensive (> 99.9%), to both human serum albumin and α-1-acid glycoprotein. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic. In vitro metabolism studies with human liver microsomes indicated that CYP 3A4 is the predominant CYP enzyme involved in tipranavir metabolism. •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): 5-6 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): 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 LD 50 in rat is over 5,000 mg/kg. Side effects include thirst and hunger, unexplained weight loss, increased urination, fatigue, and dry, itchy skin. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Aptivus •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): Tipranavir is a protease inhibitor used to treat HIV-1 resistant to more than 1 protease inhibitor. 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 Tislelizumab interact?

•Drug A: Adalimumab •Drug B: Tislelizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tislelizumab. •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): Tislelizumab is indicated as monotherapy for the treatment of unresectable, locally advanced, or metastatic esophageal squamous cell carcinoma in adults after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor, such as 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): Tislelizumab decreased tumour growth in xenograft models and a human PD-1 transgenic mouse model. •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): Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1 and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in T cells in in vitro cell-based assays. •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 pharmacokinetics (PK) of tislelizumab were characterized using population PK analysis with concentration data from 2 596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every 2 weeks, 2.0 and 5.0 mg/kg every 3 weeks, and 200 mg every 3 weeks. The time to reach 90% steady-state level is approximately 84 days (12 weeks) after 200 mg doses once every 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately 2-fold. Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable. •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): A population pharmacokinetic analysis indicates that the steady-state volume of distribution is 6.42 L, which is typical of monoclonal antibodies with limited distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available on the protein binding of tislelizumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways. •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): Based on population PK analysis, the geometrical mean terminal half-life of tislelizumab was approximately 23.8 days with a coefficient variation (CV) of 31%. •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 population PK analysis, the clearance of tislelizumab was 0.153 l/day with an interindividual variability of 26.3%. •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 available data on the use of tislelizumab in pregnant women. Based on its mechanism of action, tislelizumab can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signaling has been shown to disrupt tolerance to the fetus and result in increased fetal loss. Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing fetus. Women should be advised of the potential risk to a fetus. Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab. No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10, or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations). There is no information on overdose with tislelizumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse drug reactions, and appropriate symptomatic treatment should be instituted immediately. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tevimbra •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): Tislelizumab is an IgG4 variant monoclonal antibody against PD-1 indicated for the treatment of unresectable, locally advanced or metastatic esophageal squamous cell carcinoma

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 Tislelizumab interact? Information: •Drug A: Adalimumab •Drug B: Tislelizumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tislelizumab. •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): Tislelizumab is indicated as monotherapy for the treatment of unresectable, locally advanced, or metastatic esophageal squamous cell carcinoma in adults after prior systemic chemotherapy that did not include a PD-(L)1 inhibitor, such as 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): Tislelizumab decreased tumour growth in xenograft models and a human PD-1 transgenic mouse model. •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): Binding of the PD-1 ligands PD-L1 and PD-L2, to the PD-1 receptor found on T cells, inhibits T-cell proliferation and cytokine production. Upregulation of PD-1 ligands occurs in some tumors and signaling through this pathway can contribute to inhibition of active T-cell immune surveillance of tumors. Tislelizumab is a humanized immunoglobulin G4 (IgG4) variant monoclonal antibody against PD-1, binding to the extracellular domain of human PD-1. It competitively blocks the binding of both PD-L1 and PD-L2, inhibiting PD-1-mediated negative signalling and enhancing the functional activity in T cells in in vitro cell-based assays. •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 pharmacokinetics (PK) of tislelizumab were characterized using population PK analysis with concentration data from 2 596 patients with advanced malignancies who received tislelizumab doses of 0.5 to 10 mg/kg every 2 weeks, 2.0 and 5.0 mg/kg every 3 weeks, and 200 mg every 3 weeks. The time to reach 90% steady-state level is approximately 84 days (12 weeks) after 200 mg doses once every 3 weeks, and the steady-state accumulation ratio of tislelizumab PK exposure is approximately 2-fold. Tislelizumab is administered intravenously and therefore is immediately and completely bioavailable. •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): A population pharmacokinetic analysis indicates that the steady-state volume of distribution is 6.42 L, which is typical of monoclonal antibodies with limited distribution. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available on the protein binding of tislelizumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tislelizumab is expected to be degraded into small peptides and amino acids via catabolic pathways. •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): Based on population PK analysis, the geometrical mean terminal half-life of tislelizumab was approximately 23.8 days with a coefficient variation (CV) of 31%. •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 population PK analysis, the clearance of tislelizumab was 0.153 l/day with an interindividual variability of 26.3%. •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 available data on the use of tislelizumab in pregnant women. Based on its mechanism of action, tislelizumab can cause fetal harm when administered to a pregnant woman. Animal reproduction studies have not been conducted with tislelizumab. However, in murine models of pregnancy, blockade of PD-1/PD-L1 signaling has been shown to disrupt tolerance to the fetus and result in increased fetal loss. Human IgG4 (immunoglobulins) are known to cross the placental barrier. Therefore, tislelizumab, being an IgG4 variant, has the potential to be transmitted from the mother to the developing fetus. Women should be advised of the potential risk to a fetus. Tislelizumab should not be used during pregnancy unless the clinical condition of the woman requires treatment with tislelizumab. No clinical data are available on the possible effects of tislelizumab on fertility. No reproductive and development toxicity studies have been conducted with tislelizumab. Based on a 3-month repeat-dose toxicity study, there were no notable effects in the male and female reproductive organs in cynomolgus monkeys when tislelizumab was given at doses of 3, 10, or 30 mg/kg every 2 weeks for 13 weeks (7 dose administrations). There is no information on overdose with tislelizumab. In case of overdose, patients should be closely monitored for signs or symptoms of adverse drug reactions, and appropriate symptomatic treatment should be instituted immediately. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tevimbra •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): Tislelizumab is an IgG4 variant monoclonal antibody against PD-1 indicated for the treatment of unresectable, locally advanced or metastatic esophageal squamous cell carcinoma 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 Tisotumab vedotin interact?

•Drug A: Adalimumab •Drug B: Tisotumab vedotin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tisotumab vedotin. •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): Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after 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): Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. •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): Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to in vitro studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fcγ receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant 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): Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) C max of tisotumab vedotin-tftv was 40.8 (8.12) μg/mL and the mean (± SD) AUC was 57.5 (13.4) day x μg/mL. The mean (± SD) C max of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The C max of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle. •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 tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of MMAE ranged from 68% to 82% in vitro. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized by CYP3A4 in vitro. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv 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): The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, 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 linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv. •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 no information on the LD 50 values and overdose profile of tisotumab vedotin. Tisotumab vedotin is associated with a risk for ocular toxicity. In clinical trials, ocular adverse reactions occurred in 60% of patients with cervical cancer. The most common reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). More severe reactions included ulcerative keratitis, ulcerative keratitis with perforation requiring corneal transplantation, and symblepharon in patients with other tumor types. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tivdak •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): Tisotumab vedotin is a tissue factor-directed antibody drug conjugate that is used to treat adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.

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 Tisotumab vedotin interact? Information: •Drug A: Adalimumab •Drug B: Tisotumab vedotin •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tisotumab vedotin. •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): Tisotumab vedotin is indicated for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after 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): Tisotumab vedotin is an anticancer antibody-drug conjugate that is made up of an antibody and monomethyl auristatin E (MMAE), a cytotoxic component of the drug. It works by binding to tissue factors expressed on cervical tumours and releasing MMAE upon cell entry to mediate its cytotoxic activity. Apart from directly killing tumour cells, tisotumab vedotin may exert a bystander effect by killing neighbouring cells and promote immunogenic cell death pathways, including antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. •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): Tisotumab vedotin is a tissue factor (TF)-directed antibody-drug conjugate (ADC) anti-TF IgG1-kappa antibody conjugated to the microtubule-disrupting agent MMAE via a protease-cleavable vc (valine-citrulline) linker. It may exhibit multiple mechanisms of action; however, it primarily works by inducing cytotoxic effects on TF-expressing tumours. Tisotumab vedotin binds to TFs expressed on cervical tumours, which leads to the internalization of the antibody-drug conjugate-TF complex. Once internalized, MMAE from the drug-target complex is released via proteolytic cleavage. MMAE is a microtubule-disrupting agent that disrupts the microtubule network of actively dividing cells, leading to cell cycle arrest and apoptotic cell death. Tisotumab vedotin may also promote bystander killing of neighbouring cells. According to in vitro studies, tisotumab vedotin induces immunogenic cell death and promotes tumour cell death through Fcγ receptor-mediated effector functions, such as antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis. Tisotumab vedotin may inhibit TF-activated factor VII (FVIIa)–dependent intracellular signalling, with negligent effects on procoagulant 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): Following administration of one 3-week cycle of tisotumab vedotin-tftv 2 mg/kg, the peak concentrations reached near the end of the infusion, while unconjugated MMAE concentrations peaked approximately two to three days after tisotumab vedotin-tftv dosing. The mean (± SD) C max of tisotumab vedotin-tftv was 40.8 (8.12) μg/mL and the mean (± SD) AUC was 57.5 (13.4) day x μg/mL. The mean (± SD) C max of unconjugated MMAE was 5.91 (4.2) ng/mL and the mean (± SD) AUC was 50 (35.8) day x ng/mL. The C max of tisotumab vedotin-tftv increased proportionally and there was no drug accumulation. Steady-state concentrations of tisotumab vedotin-tftv and unconjugated MMAE were reached after one treatment cycle. •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 tisotumab vedotin-tftv steady-state volume of distribution is 7.83 (%CV: 19.1) L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Plasma protein binding of MMAE ranged from 68% to 82% in vitro. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tisotumab vedotin-tftv most likely undergoes catabolism to form small peptides, amino acids, unconjugated MMAE, and unconjugated MMAE-related catabolites. Via proteolytic cleavage, tisotumab vedotin-tftv releases unconjugated MMAE, which is primarily metabolized by CYP3A4 in vitro. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The excretion of tisotumab vedotin-tftv is not fully characterized. Following a single-dose of another antibody-drug conjugate that contains MMAE, 17% of the total MMAE administered was recovered in feces and 6% in urine over a 1-week period, primarily as unchanged drug. A similar excretion profile of MMAE is expected after tisotumab vedotin-tftv 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): The median terminal half-life of tisotumab vedotin-tftv and unconjugated MMAE is 4.04 (range: 2.26-7.25) days and 2.56 (range: 1.81-4.10) days, 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 linear clearance of tisotumab vedotin-tftv and unconjugated MMAE was 1.54 (%CV: 28.8) L/day and 45.9 (%CV: 61.1) L/day, respectively. Elimination of MMAE appeared to be limited by its rate of release from tisotumab vedotin-tftv. •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 no information on the LD 50 values and overdose profile of tisotumab vedotin. Tisotumab vedotin is associated with a risk for ocular toxicity. In clinical trials, ocular adverse reactions occurred in 60% of patients with cervical cancer. The most common reactions were conjunctival adverse reactions (40%), dry eye (29%), corneal adverse reactions (21%), and blepharitis (8%). More severe reactions included ulcerative keratitis, ulcerative keratitis with perforation requiring corneal transplantation, and symblepharon in patients with other tumor types. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tivdak •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): Tisotumab vedotin is a tissue factor-directed antibody drug conjugate that is used to treat adults with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. 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 Tixocortol interact?

•Drug A: Adalimumab •Drug B: Tixocortol •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tixocortol. •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): Tixocortol is indicated for the treatment of rhinitis as a nasal suspension or aerosol. It is also used in the form of lozenges for the treatment of pharyngitis and in the form of enemas or rectal solution for the treatment of ulcerative colitis. Tixocortol can be used orally in a suspension or powder for the treatment of inflammatory conditions. It is also the substance used for the screening of contact allergies to class A steroids. •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): Tixocortol presents the characteristic of local action which reduces significantly the side effects of systemic glucocorticoids. Reports have demonstrated that gastrointestinal administration of tixocortol generates a decrease in abdominal pain, bleeding, and frequency of stools which resulted in an amelioration in the malabsorption laboratory tests. All the effects were independent of suppression of the pituitary-adrenal axis, which was shown by the absence of significant depression of cortisol. Administration of tixocortol as a nasal spray has been shown to respect nasal drainage by the ciliary beats of the pituitary mucosa. The actions of tixocortol have no effect on leukocyte count, blood glucose level, sodium urinary excretion, and immunosupressive activity on lymphocytes. •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 tixocortol is similar to other corticosteroids regarding the binding sites and prostaglandin synthesis but the local properties of tixocortol are given by the immediate liver metabolism and transformation withing red blood cells. All the immediate transformations of tixocortol classified it as part of the nonsystemic steroids. •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 tixocortol is the same as in other steroids including hydrocortisone. Oral administration of tixocortol presents a 10-20% bioavailability with a significantly lower plasma Cmax than cortisol. The fast metabolism, larger volume of distribution and low bioavailability donates tixocortol with the absence of systemic activity. •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): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger volume of distribution compared to cortisol of 21.7 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The presence of the C-17 in the corticosteroids is a protein binding site. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tixocortol is rapidly modified within red blood cells and it is immediately metabolized by a first-pass liver metabolism. The metabolites of tixocortol are mainly represented by the formation of sulfo- and glucurono-conjugates which are later hydrolyzed from the conjugate forming neutral steroids. The metabolic transformations are the reduction of the 3-keto and delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol and cleavage of the side chain at C-17. The specific metabolic pathways of the C-21 thiol ester function were its transformation into methylthio, methylsulfonyl and methylsulfonyl derivatives and reductive cleavage of the C-21-S bond leading to 21-methyl structures. None of the metabolites have affinity for glucocorticoid receptors. This and the extensive metabolism explains the exclusive local activities of tixocortol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tixocortol has a rapid elimination after continuous metabolism. Urine analysis of oral administration of tixocortol demonstrate a complete lack 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): Tixocortol presents a shorter half-life than cortisol. •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): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger clearance rate compared to cortisol of 33.3 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): Diverse studies performed on tixocortol proved that this drug is non-toxic and non-immunosupressive. This low toxicity and abscence of immuno supression gave tixocortol the potential to be a lead for topical or local anti-inflammatory treatments. Nevertheless, toxicortol is a potent cutaneous sensitizer, causing a local allergy. •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): Tixocortol is a corticosteroid used for the symptomatic treatment of rhinitis, pharyngitis, 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 Tixocortol interact? Information: •Drug A: Adalimumab •Drug B: Tixocortol •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tixocortol. •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): Tixocortol is indicated for the treatment of rhinitis as a nasal suspension or aerosol. It is also used in the form of lozenges for the treatment of pharyngitis and in the form of enemas or rectal solution for the treatment of ulcerative colitis. Tixocortol can be used orally in a suspension or powder for the treatment of inflammatory conditions. It is also the substance used for the screening of contact allergies to class A steroids. •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): Tixocortol presents the characteristic of local action which reduces significantly the side effects of systemic glucocorticoids. Reports have demonstrated that gastrointestinal administration of tixocortol generates a decrease in abdominal pain, bleeding, and frequency of stools which resulted in an amelioration in the malabsorption laboratory tests. All the effects were independent of suppression of the pituitary-adrenal axis, which was shown by the absence of significant depression of cortisol. Administration of tixocortol as a nasal spray has been shown to respect nasal drainage by the ciliary beats of the pituitary mucosa. The actions of tixocortol have no effect on leukocyte count, blood glucose level, sodium urinary excretion, and immunosupressive activity on lymphocytes. •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 tixocortol is similar to other corticosteroids regarding the binding sites and prostaglandin synthesis but the local properties of tixocortol are given by the immediate liver metabolism and transformation withing red blood cells. All the immediate transformations of tixocortol classified it as part of the nonsystemic steroids. •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 tixocortol is the same as in other steroids including hydrocortisone. Oral administration of tixocortol presents a 10-20% bioavailability with a significantly lower plasma Cmax than cortisol. The fast metabolism, larger volume of distribution and low bioavailability donates tixocortol with the absence of systemic activity. •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): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger volume of distribution compared to cortisol of 21.7 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The presence of the C-17 in the corticosteroids is a protein binding site. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tixocortol is rapidly modified within red blood cells and it is immediately metabolized by a first-pass liver metabolism. The metabolites of tixocortol are mainly represented by the formation of sulfo- and glucurono-conjugates which are later hydrolyzed from the conjugate forming neutral steroids. The metabolic transformations are the reduction of the 3-keto and delta 4 system, reduction of the C-20 carbonyl group, oxidation of the C-11 alcohol and cleavage of the side chain at C-17. The specific metabolic pathways of the C-21 thiol ester function were its transformation into methylthio, methylsulfonyl and methylsulfonyl derivatives and reductive cleavage of the C-21-S bond leading to 21-methyl structures. None of the metabolites have affinity for glucocorticoid receptors. This and the extensive metabolism explains the exclusive local activities of tixocortol. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tixocortol has a rapid elimination after continuous metabolism. Urine analysis of oral administration of tixocortol demonstrate a complete lack 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): Tixocortol presents a shorter half-life than cortisol. •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): Studies have shown that oral or intravenous administration of tixocortol presents a significantly larger clearance rate compared to cortisol of 33.3 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): Diverse studies performed on tixocortol proved that this drug is non-toxic and non-immunosupressive. This low toxicity and abscence of immuno supression gave tixocortol the potential to be a lead for topical or local anti-inflammatory treatments. Nevertheless, toxicortol is a potent cutaneous sensitizer, causing a local allergy. •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): Tixocortol is a corticosteroid used for the symptomatic treatment of rhinitis, pharyngitis, 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 Tizanidine interact?

•Drug A: Adalimumab •Drug B: Tizanidine •Severity: MAJOR •Description: The metabolism of Tizanidine 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): Tizanidine is indicated for the relief of muscle spasticity, which can interfere with daily activities. The general recommendation is to reserve tizanidine use for periods of time when there is a particular need for relief, as it has a short duration of action. •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): A note on spasticity Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. General effects Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. Effects on blood pressure and heart rate This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued. •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): Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular 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): This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40%. Effect of food on absorption Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. It is therefore advisable to take this drug with food for increased absorption, especially in tablet form. •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): Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 30% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): This drug is mainly eliminated by the kidney. •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 2.5 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): A note on renal impairment Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with 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): LD50 information Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg Use in pregnancy Animal studies have determined that this drug causes fetal harm. Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child. Use in breastfeeding In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1. In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk. Carcinogenesis and mutagenesis No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group. Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zanaflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tizanidin Tizanidina Tizanidine Tizanidinum •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): Tizanidine is an alpha-2 adrenergic agonist used for the short-term treatment of muscle spasticity.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tizanidine interact? Information: •Drug A: Adalimumab •Drug B: Tizanidine •Severity: MAJOR •Description: The metabolism of Tizanidine 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): Tizanidine is indicated for the relief of muscle spasticity, which can interfere with daily activities. The general recommendation is to reserve tizanidine use for periods of time when there is a particular need for relief, as it has a short duration of action. •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): A note on spasticity Spasticity is an increase in muscle accompanied by uncontrolled, repetitive contractions of skeletal muscles which are involuntary. The patient suffering from muscle spasticity may have reduced mobility and high levels of pain, contributing to poor quality of life and problems performing activities of personal hygiene and care. General effects Tizanidine is a rapidly acting drug used for the relief of muscle spasticity when it is required for performing specific activities. It acts as an agonist at Alpha-2 adrenergic receptor sites and relieves symptoms of muscle spasticity, allowing the continuation of normal daily activities. In animal models, tizanidine has not been shown to exert direct effects on skeletal muscle fibers or the neuromuscular junction, and has shown no significant effect on monosynaptic spinal reflexes (consisting of the communication between only 1 sensory neuron and 1 motor neuron). The frequency of muscle spasm and clonus are shown to be decreased by tizanidine. Tizanidine shows a stronger action on polysynaptic reflexes, which involve several interneurons (relay neurons) communicating with motor neurons stimulating muscle movement. Effects on blood pressure and heart rate This drug decreases heart rate and blood pressure in humans. Despite this, rebound hypertension and tachycardia along with increased spasticity can occur when tizanidine is abruptly discontinued. •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): Tizanidine reduces spasticity by causing presynaptic inhibition of motor neurons via agonist actions at Alpha-2 adrenergic receptor sites. This drug is centrally acting and leads to a reduction in the release of excitatory amino acids like glutamate and aspartate, which cause neuronal firing that leads to muscle spasm. The above reduction and excitatory neurotransmitter release results in presynaptic inhibition of motor neurons. The strongest effect of tizanidine has been shown to occur on spinal polysynaptic pathways. The anti-nociceptive and anticonvulsant activities of tizanidine may also be attributed to agonist action on Alpha-2 receptors. Tizanidine also binds with weaker affinity to the Alpha-1 receptors, explaining its slight and temporary effect on the cardiovascular 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): This drug undergoes significant first-pass metabolism. After the administration of an oral dose, tizanidine is mostly absorbed. The absolute oral bioavailability of tizanidine is measured to be about 40%. Effect of food on absorption Food has been shown to increase absorption for both the tablets and capsules. The increase in absorption with the tablet (about 30%) was noticeably higher than the capsule (~10%). When the capsule and tablet were administered with food, the amount absorbed from the capsule was about 80% of the amount absorbed from the tablet. It is therefore advisable to take this drug with food for increased absorption, especially in tablet form. •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): Extensively distributed throughout the body. The average steady-state volume of distribution is 2.4 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 30% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): About 95% of the ingested dose of tizanidine is metabolized. The main enzyme involved in the hepatic metabolism of tizanidine is CYP1A2. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): This drug is mainly eliminated by the kidney. •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 2.5 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): A note on renal impairment Tizanidine clearance is found to be decreased by more than 50% in elderly patients with renal insufficiency (creatinine clearance < 25 mL/min) compared to healthy elderly subjects; this would be expected to lead to a longer duration of clinical effect. This drug should be used with caution in patients with 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): LD50 information Oral LD50 (rat): 414 mg/kg; Subcutaneous LD50 (rat): 282 mg/kg; Oral LD50 (mouse): 235 mg/kg Use in pregnancy Animal studies have determined that this drug causes fetal harm. Studies have not been performed in humans, and it is advisable to ensure that tizanidine use in pregnant women should be reserved for cases in which possible benefit clearly outweighs the possible risk to mother and unborn child. Use in breastfeeding In studies of rat models, this tizanidine was found excreted in the breastmilk with a milk-to-blood ratio of 1.8:1. In young nursing rats, abnormal results were obtained in tests indicative of central nervous system function. Various developmental changes that may have been attributable to the drug were observed. It is unknown whether tizanidine is excreted in human milk. It is a lipid-soluble drug, however, and likely to be excreted into breast milk. Carcinogenesis and mutagenesis No signs of carcinogenicity were observed in two dietary studies performed in rodent models. Tizanidine was given to mice for 78 weeks at doses reaching a maximum 16 mg/kg (equivalent to twice the maximum recommended human dose). In addition, the drug was given to rats for 104 weeks at doses reaching 9 mg/kg (equivalent to 2.5 times the maximum recommended human dose). There was a lack of a statistically significant increase in the occurrence of tumors in either study group. Tizanidine was not found to be mutagenic or clastogenic in several laboratory essays, including the bacterial Ames test, the mammalian gene mutation test, in addition to the chromosomal aberration test in Chinese hamster cells and several other assays. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Zanaflex •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tizanidin Tizanidina Tizanidine Tizanidinum •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): Tizanidine is an alpha-2 adrenergic agonist used for the short-term treatment of muscle spasticity. 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 Tocilizumab interact?

•Drug A: Adalimumab •Drug B: Tocilizumab •Severity: MAJOR •Description: Tocilizumab may increase the immunosuppressive activities of Adalimumab. •Extended Description: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients is associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, infections due to immunosuppression are also one of the most common adverse effects associated with the use of the IL-6 antagonist, tocilizumab . As a result, if tocilizumab is used concomitantly with TNF-α inhibitors, there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections, lymphoma, and/or other malignancies . In particular, tocilizumab has specifically not been studied in combination with TNF antagonists (among many other immunosuppressive agents) because of the proposed possibility of increased and severe immunosuppression and risk of infection . •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): Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). •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): Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. •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): Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. •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 162mg subcutaneous dose given weekly has a C max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C max of 154±42µg/mL and an AUC of 39216±14304µg*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): In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the serum protein binding of tocilizumab is not readily available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tocilizumab, like other monoclonal antibodies, is 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): Data regarding the exact route of elimination of monoclonal antibodies is not readily 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 half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 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 linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher 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): Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Actemra, RoActemra •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): Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA).

Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients is associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, infections due to immunosuppression are also one of the most common adverse effects associated with the use of the IL-6 antagonist, tocilizumab . As a result, if tocilizumab is used concomitantly with TNF-α inhibitors, there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections, lymphoma, and/or other malignancies . In particular, tocilizumab has specifically not been studied in combination with TNF antagonists (among many other immunosuppressive agents) because of the proposed possibility of increased and severe immunosuppression and risk of infection . The severity of the interaction is major.

Question: Does Adalimumab and Tocilizumab interact? Information: •Drug A: Adalimumab •Drug B: Tocilizumab •Severity: MAJOR •Description: Tocilizumab may increase the immunosuppressive activities of Adalimumab. •Extended Description: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients is associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, infections due to immunosuppression are also one of the most common adverse effects associated with the use of the IL-6 antagonist, tocilizumab . As a result, if tocilizumab is used concomitantly with TNF-α inhibitors, there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections, lymphoma, and/or other malignancies . In particular, tocilizumab has specifically not been studied in combination with TNF antagonists (among many other immunosuppressive agents) because of the proposed possibility of increased and severe immunosuppression and risk of infection . •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): Tocilizumab is indicated to treat moderate to severe rheumatoid arthritis, giant cell arteritis, systemic sclerosis-associated interstitial lung disease, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis, and cytokine release syndrome. Tocilizumab is also used to treat coronavirus disease 2019 (COVID-19) in adults who are receiving systemic corticosteroids and require supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO). •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): Tocilizumab is an IL-6 inhibiting monoclonal antibody used to treat autoimmune and inflammatory conditions. Tocilizumab has a long duration of action as it is generally given every 4 weeks and has a wide therapeutic index. Patients should be counselled regarding the risk of infections, GI perforation, and hepatotoxicity. •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): Interleukin 6 (IL-6) is a pro-inflammatory cytokine produced by cells including T-cells, B-cells, lymphocytes, monocytes, fibroblasts. IL-6 rapidly induces C-reactive protein, serum amyloid A, fibrinogen, haptoglobin, and α-1-antichymotrypsin while inhibiting production of fibronectin, albumin, and transferrin. IL-6 also induces antibody production, induces cytotoxic T-cell differentiation, and inhibits regulatory T-cell differentiation. Tocilizumab binds soluble and membrane bound IL-6 receptors, preventing IL-6 mediated inflammation. •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 162mg subcutaneous dose given weekly has a C max of 51.3±23.2µg/mL and an AUC of 8254±3833µg*h/mL. A 162mg subcutaneous dose given every 2 weeks has a C max of 13±8.3µg/mL and an AUC of 3460±2530µg*h/mL. A 162mg subcutaneous dose given every 4 weeks has a C max of 154±42µg/mL and an AUC of 39216±14304µg*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): In rheumatoid arthritis patients, the central volume of distribution is 3.5L, the peripheral volume of distribution is 2.9L, and the volume of distribution at steady state is 6.4L. In giant cell arteritis patients, the central volume of distribution is 4.09L, the peripheral volume of distribution if 3.37L, and the volume of distribution at steady state is 7.46L. In pediatric patients with polyarticular juvenile arthritis, the central volume of distribution is 1.98L, the peripheral volume of distribution is 2.1L, and the volume of distribution at steady state is 4.08L. In pediatric patients with systemic juvenile idiopathic arthritis, the central volume of distribution is 1.87L, the peripheral volume of distribution is 2.14L, and the volume of distribution at steady state is 4.01L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Data regarding the serum protein binding of tocilizumab is not readily available. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tocilizumab, like other monoclonal antibodies, is 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): Data regarding the exact route of elimination of monoclonal antibodies is not readily 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 half life of tocilizumab is concentration dependent. The terminal half life in rheumatoid arthritis patients is 21.5 days. The absorption half life in rheumatoid arthritis and giant cell arteritis patients was 4 days, and in polyarticular juvenile idiopathic arthritis patients and systemic juvenile idiopathic arthritis patients was 2 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 linear clearance in rheumatoid arthritis patients is 12.5mL/h, in giant cell arteritis patients is 6.7mL/h, in polyarticular juvenile idiopathic arthritis patients is 5.8mL/h, and in systemic juvenile idiopathic arthritis is 5.7mL/h. Clearance is dose dependent and changes from non linear at low doses to linear at higher 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): Data regarding overdoses of tocilizumab are not readily available. Patients experiencing an overdose may develop neutropenia. In case of overdose, monitor patients for signs of adverse reactions and provide symptomatic and supportive treatment. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Actemra, RoActemra •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): Tocilizumab is an interleukin-6 (IL-6) receptor antagonist used to treat Cytokine Release Syndrome (CRS), Systemic Juvenile Idiopathic Arthritis (sJIA), Giant Cell Arteritis (GCA), and Rheumatoid Arthritis (RA). Output: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients is associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, infections due to immunosuppression are also one of the most common adverse effects associated with the use of the IL-6 antagonist, tocilizumab . As a result, if tocilizumab is used concomitantly with TNF-α inhibitors, there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections, lymphoma, and/or other malignancies . In particular, tocilizumab has specifically not been studied in combination with TNF antagonists (among many other immunosuppressive agents) because of the proposed possibility of increased and severe immunosuppression and risk of infection . The severity of the interaction is major.

Does Adalimumab and Tofacitinib interact?

•Drug A: Adalimumab •Drug B: Tofacitinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tofacitinib. •Extended Description: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients are associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, because infection as a result of immunosuppression is also one of the most common adverse effects associated with the use of the Janus kinase inhibitor tofacitinib . As a result, if tofacitinib is used concomitantly with a TNF-α inhibitor(s), there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections for the patient . •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): Tofacitinib is indicated for the treatment of adult patients with moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers. It is also indicated as an oral solution in patients ≥2 years of age for the treatment of polyarticular course juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Tofacitinib is not recommended to be used in combination with other biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressive agents such as azathioprine or cyclosporine. •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): Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life. •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): Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well. •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): 74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max ) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%. •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= 87L after intravenous administration. Distribution is equal between red blood cells and plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 40%, mostly bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated 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): ~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): 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): Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking. Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. Role of JAK inhibition in the development of gastrointestinal perforation is not known. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Xeljanz •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): Tofacitinib is a Janus kinase (JAK) inhibitor used to treat rheumatic conditions, such as rheumatoid arthritis and ankylosing spondylitis, and ulcerative colitis.

Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients are associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, because infection as a result of immunosuppression is also one of the most common adverse effects associated with the use of the Janus kinase inhibitor tofacitinib . As a result, if tofacitinib is used concomitantly with a TNF-α inhibitor(s), there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections for the patient . The severity of the interaction is major.

Question: Does Adalimumab and Tofacitinib interact? Information: •Drug A: Adalimumab •Drug B: Tofacitinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tofacitinib. •Extended Description: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients are associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, because infection as a result of immunosuppression is also one of the most common adverse effects associated with the use of the Janus kinase inhibitor tofacitinib . As a result, if tofacitinib is used concomitantly with a TNF-α inhibitor(s), there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections for the patient . •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): Tofacitinib is indicated for the treatment of adult patients with moderately-to-severely active rheumatoid arthritis (RA), active psoriatic arthritis, active ankylosing spondylitis, or moderately-to-severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers. It is also indicated as an oral solution in patients ≥2 years of age for the treatment of polyarticular course juvenile idiopathic arthritis who have had an inadequate response or intolerance to one or more TNF blockers. Tofacitinib is not recommended to be used in combination with other biologic disease-modifying anti-rheumatic drugs (DMARDs) or potent immunosuppressive agents such as azathioprine or cyclosporine. •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): Tofacitinib targets inflammation present in rheumatoid arthritis by inhibiting the janus kinases involved in the inflammatory response pathway. In placebo controlled trials of rheumatoid arthritis patients receiving 5mg or 10mg of tofacitinib twice daily, higher ACR20 responses were observed within 2 weeks in some patients (with ACR20 being defined as a minimum 20% reduction in joint pain or tenderness and 20% reduction in arthritis pain, patient disability, inflammatory markers, or global assessments of arthritis by patients or by doctors, according to the American College of Rheumatology (ACR) response criteria list), and improvements in physical functioning greater than placebo were also noted. Common known adverse effects of tofacitinib include headaches, diarrhea, nausea, nasopharyngitis and upper respiratory tract infection. More serious immunologic and hematological adverse effects have also been noted resulting in lymphopenia, neutropenia, anemia, and increased risk of cancer and infection. Before initiations of tofacitinib patients should be tested for latent infections of tuberculosis, and should be closely monitored for signs and symptoms of infection (fungal, viral, bacterial, or mycobacterial) during therapy. Therapy is not to be started in the presence of active infection, systemic or localized, and is to be interrupted if a serious infection occurs. Tofacitinib has been associated with an increased risk of lymphomas, such as Epstein-Barr virus associated lymphomas, and other malignancies (including lung, breast, gastric, and colorectal cancers). It is recommended to monitor lymphocytes, neutrophils, hemoglobin, liver enzymes, and lipids. Tofacitinib use is associated with a rapid decrease in C-reactive protein (CRP), dose dependent decreases in natural killer cells, and dose dependent increases in B cells. Depression in C-reactive protein levels continue after 2 weeks of tofacitinib discontinuation and suggest that pharmacodynamic activity last longer than pharmacokinetic half life. •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): Rheumatoid arthritis is an autoimmune disease characterized by a dysregulation of pro-inflammatory cytokines including IL7, IL15, IL21, IL6, IFN-alpha, and IFN-beta. (3) Cytokines signalling results in tissue inflammation and joint damage by stimulating the recruitment and activation of immune cells via the janus kinase signalling pathway. Tofacitinib is a partial and reversible janus kinase (JAK) inihibitor that will prevent the body from responding to cytokine signals. By inhibiting JAKs, tofacitinib prevents the phosphorylation and activation of STATs. The JAK-STAT signalling pathway is involved in the transcription of cells involved in hematopoiesis, and immune cell function. Tofacitinib works therapeutically by inhibiting the JAK-STAT pathway to decrease the inflammatory response. However, there is evidence to suggest that it may also achieve efficacy via other pathways as well. •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): 74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max ) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%. •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= 87L after intravenous administration. Distribution is equal between red blood cells and plasma. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 40%, mostly bound to albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): 70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated 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): ~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): 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): Minimum lethal dose in rat: 500 mg/kg. Maximum asymptomatic dose in non human primate: 40 mg/kg. Lymphatic, immune system, bone marrow and erythroid cell toxicity was seen in animal studies involving rate and monkeys. Doses used in these studies ranged from 1mg/kg/day to 10mg/kg/day, over a duration of 6 weeks to 6 months. Lymphopenia, neutropenia, and anemia is seen in human subjects and may call for an interruption or discontinuation of therapy if severe. Reduced female fertility in rats was seen at exposures 17 times the maximum recommended human dose. Fertility may be impaired in human females and harm may be caused to unborn child. Carcinogenic potential is seen, however evidence for dose dependency is lacking. Because the janus kinase pathway plays a role in stimulating the production of red blood cells and is involved in immune cell function, inhibition of this pathway leads to increased risk of anemia, neutropenia, lymphopenia, cancer and infection. Lymphopenia, neutropenia, and anemia in human subjects may call for an interruption or discontinuation of therapy if severe. Role of JAK inhibition in the development of gastrointestinal perforation is not known. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Xeljanz •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): Tofacitinib is a Janus kinase (JAK) inhibitor used to treat rheumatic conditions, such as rheumatoid arthritis and ankylosing spondylitis, and ulcerative colitis. Output: Various clinical studies have shown that the use of tumor necrosis factor alpha (TNF-α) inhibitors in patients are associated with the possibility of developing infections, lymphoma, and/or other malignancies, some incidences of which can be fatal . At the same time, because infection as a result of immunosuppression is also one of the most common adverse effects associated with the use of the Janus kinase inhibitor tofacitinib . As a result, if tofacitinib is used concomitantly with a TNF-α inhibitor(s), there is a concern that the combined, additive immunosuppressive effects of both types of medications can subsequently cause an increased risk, incidence, or severity of infections for the patient . The severity of the interaction is major.

Does Adalimumab and Tolazamide interact?

•Drug A: Adalimumab •Drug B: Tolazamide •Severity: MODERATE •Description: The metabolism of Tolazamide 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 use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. •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): Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. •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 likely bind to ATP-sensitive potassium-channel receptors 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): Rapidly and well 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): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally 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 average biological half-life of the drug is 7 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 of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tolinase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolazamid Tolazamida Tolazamide Tolazamidum •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): Tolazamide 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 Tolazamide interact? Information: •Drug A: Adalimumab •Drug B: Tolazamide •Severity: MODERATE •Description: The metabolism of Tolazamide 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 use as an adjunct to diet to lower the blood glucose in patients with non-insulin dependent diabetes mellitus (Type II) whose hyperglycemia cannot be satisfactorily controlled by diet alone. •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): Tolazamide is an oral blood glucose lowering drug of the sulfonylurea class. Tolazamide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which tolazamide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. Some patients who are initially responsive to oral hypoglycemic drugs, including tolazamide, may become unresponsive or poorly responsive over time. Alternatively, tolazamide may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, tolazamide produces a mild diuresis by enhancement of renal free water clearance. •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 likely bind to ATP-sensitive potassium-channel receptors 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): Rapidly and well 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): No protein binding available •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0 to 70%. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tolazamide is metabolized to five major metabolites ranging in hypoglycemic activity from 0% to 70%. They are excreted principally 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 average biological half-life of the drug is 7 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 of sulfonylureas can produce hypoglycemia. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tolinase •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolazamid Tolazamida Tolazamide Tolazamidum •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): Tolazamide 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 Tolbutamide interact?

•Drug A: Adalimumab •Drug B: Tolbutamide •Severity: MODERATE •Description: The metabolism of Tolbutamide 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 (non-insulin-dependent diabetes mellitus) 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): Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. •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 lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. •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 following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. •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): Approximately 95% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 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 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. •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 = 2600 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): Tolbutamida Tolbutamide Tolbutamidum Tolylsulfonylbutylurea •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): Tolbutamide is a sulfonylurea used to treat hyperglycemia in patients with type 2 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 Tolbutamide interact? Information: •Drug A: Adalimumab •Drug B: Tolbutamide •Severity: MODERATE •Description: The metabolism of Tolbutamide 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 (non-insulin-dependent diabetes mellitus) 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): Tolbutamide, a first-generation sulfonylurea antidiabetic agent, is used with diet to lower blood glucose levels in patients with diabetes mellitus type II. Tolbutamide is twice as potent as the related second-generation agent glipizide. Tolbutamide lowers blood sugar by stimulating the pancreas to secrete insulin and helping the body use insulin efficiently. The pancreas must be able to produce insulin for this drug to work. •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 lower blood glucose in patients with NIDDM by directly stimulating the acute release of insulin from functioning beta cells of pancreatic islet tissue by an unknown process that involves a sulfonylurea receptor (receptor 1) on the beta cell. Sulfonylureas inhibit the ATP-potassium channels on the beta cell membrane and potassium efflux, which results in depolarization and calcium influx, calcium-calmodulin binding, kinase activation, and release of insulin-containing granules by exocytosis, an effect similar to that of glucose. •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 following oral administration. Tolbutamide is detectable in plasma 30-60 minutes following oral administration of a single dose with peak plasma concentrations occurring within 3-5 hours. Absorption is unaltered if taken with food but is increased with high pH. •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): Approximately 95% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolized in the liver principally via oxidation of the p-methyl group producing the carboxyl metabolite, 1-butyl-3-p-carboxyphenylsulfonylurea. May also be metabolized to hydroxytolbutamide. Tolbutamide does not undergo acetylation like antibacterial sulfonamides as it does not have a p-amino group. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Unchanged drug and metabolites are eliminated in the urine and feces. Approximately 75-85% of a single orally administered dose is excreted in the urine principally as the 1-butyl-3-p-carboxyphenylsulfonylurea within 24 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 7 hours with interindividual variations ranging from 4-25 hours. Tolbutamide has the shortest duration of action, 6-12 hours, of the antidiabetic sulfonylureas. •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 = 2600 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): Tolbutamida Tolbutamide Tolbutamidum Tolylsulfonylbutylurea •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): Tolbutamide is a sulfonylurea used to treat hyperglycemia in patients with type 2 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 Tolterodine interact?

•Drug A: Adalimumab •Drug B: Tolterodine •Severity: MODERATE •Description: The metabolism of Tolterodine 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 of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence). •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): Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary 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): Both tolterodine and its active metabolite, 5-hydroxymethyltolterodine, act as competitive antagonists at muscarinic receptors. This antagonism results in inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder. •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): 113 ± 26.7 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 96.3%. •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): Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 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): 1.9-3.7 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): Detrol, Detrusitol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolterodina Tolterodine Tolterodinum •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): Tolterodine is a muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tolterodine interact? Information: •Drug A: Adalimumab •Drug B: Tolterodine •Severity: MODERATE •Description: The metabolism of Tolterodine 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 of overactive bladder (with symptoms of urinary frequency, urgency, or urge incontinence). •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): Tolterodine is a competitive muscarinic receptor antagonist. Both urinary bladder contraction and salivation are mediated via cholinergic muscarinic receptors. After oral administration, tolterodine is metabolized in the liver, resulting in the formation of the 5-hydroxymethyl derivative, a major pharmacologically active metabolite. The 5-hydroxymethyl metabolite, which exhibits an antimuscarinic activity similar to that of tolterodine, contributes significantly to the therapeutic effect. Both tolterodine and the 5-hydroxymethyl metabolite exhibit a high specificity for muscarinic receptors, since both show negligible activity or affinity for other neurotransmitter receptors and other potential cellular targets, such as calcium channels. Tolterodine has a pronounced effect on bladder function. The main effects of tolterodine are an increase in residual urine, reflecting an incomplete emptying of the bladder, and a decrease in detrusor pressure, consistent with an antimuscarinic action on the lower urinary 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): Both tolterodine and its active metabolite, 5-hydroxymethyltolterodine, act as competitive antagonists at muscarinic receptors. This antagonism results in inhibition of bladder contraction, decrease in detrusor pressure, and an incomplete emptying of the bladder. •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): 113 ± 26.7 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 96.3%. •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): Following administration of a 5-mg oral dose of 14C-tolterodine solution to healthy volunteers, 77% of radioactivity was recovered in urine and 17% was recovered in feces in 7 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): 1.9-3.7 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): Detrol, Detrusitol •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Tolterodina Tolterodine Tolterodinum •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): Tolterodine is a muscarinic receptor antagonist used to treat overactive bladder with urinary incontinence, urgency, and frequency. 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 Tolvaptan interact?

•Drug A: Adalimumab •Drug B: Tolvaptan •Severity: MAJOR •Description: The metabolism of Tolvaptan 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): Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and 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): Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 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): Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin. •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): Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan. •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): Healthy subjects: 3L/kg; slightly higher in heart failure patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Fecal- very little renal elimination (<1% 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): Terminal half life, oral dose = 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): 4 mL/min/kg (post-oral 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): The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Jinarc, Jynarque 45/15 Carton, Samsca •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): Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tolvaptan interact? Information: •Drug A: Adalimumab •Drug B: Tolvaptan •Severity: MAJOR •Description: The metabolism of Tolvaptan 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): Treatment of symptomatic and resistant to fluid restriction euvolemic or hypervolemic hyponatremia associated with congestive heart failure, SIADH, and 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): Urine volume and fluid intake increase in a dose dependent manner which results in overall negative fluid balance in patients taking tolvaptan. Increases in serum sodium and osmolality can be observed 4-8 hours post-administration and is maintained for 24 hours. The magnitude of serum sodium and osmolality change increases with escalating doses. Furthermore, a decrease in urine osmolality and increase in free water clearance can be observed 4 hours after post-administration of tolvaptan. The affinity for V2 receptors is 29x greater than that of V1a receptors and does not have any appreciable affinity for V2 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): Tolvaptan is a selective and competitive arginine vasopressin receptor 2 antagonist. Vasopressin acts on the V2 receptors found in the walls of the vasculature and luminal membranes of renal collecting ducts. By blocking V2 receptors in the renal collecting ducts, aquaporins do not insert themselves into the walls thus preventing water absorption. This action ultimately results in an increase in urine volume, decrease urine osmolality, and increase electrolyte-free water clearance to reduce intravascular volume and an increase serum sodium levels. Tolvaptan is especially useful for heart failure patients as they have higher serum levels of vasopressin. •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): Tmax, Healthy subjects: 2 - 4 hours; Cmax, Healthy subjects, 30 mg: 374 ng/mL; Cmax, Healthy subjects, 90 mg: 418 ng/mL; Cmax, heart failure patients, 30 mg: 460 ng/mL; Cmax, heart failure patients, 90 mg: 723 ng/mL; AUC(0-24 hours), 60 mg: 3.71 μg·h/mL; AUC(∞), 60 mg: 4.55 μg·h/mL; The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Food does not impact the bioavailability of tolvaptan. •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): Healthy subjects: 3L/kg; slightly higher in heart failure patients. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 99% bound •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Metabolism exclusively by CYP3A4 enzyme in the liver. Metabolites are inactive. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Fecal- very little renal elimination (<1% 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): Terminal half life, oral dose = 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): 4 mL/min/kg (post-oral 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): The oral LD50 of tolvaptan in rats and dogs is >2000 mg/kg. Most common adverse reactions (≥5% placebo) are thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria, and hyperglycemia. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Jinarc, Jynarque 45/15 Carton, Samsca •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): Tolvaptan is a selective vasopressin V2-receptor antagonist to slow kidney function decline in patients at risk for rapidly progressing autosomal dominant polycystic kidney disease (ADPKD). Also used to treat hypervolemic and euvolemic hyponatremia. 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 Topotecan interact?

•Drug A: Adalimumab •Drug B: Topotecan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Topotecan. •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 advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation 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): Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug. •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): Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. •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): 35% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 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): 2-3 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): 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 primary anticipated complication of overdosage would consist of bone marrow suppression. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Hycamtin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Topotecan Topotecane Topotecanum •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): Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical 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 Topotecan interact? Information: •Drug A: Adalimumab •Drug B: Topotecan •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Topotecan. •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 advanced ovarian cancer in patients with disease that has recurred or progressed following therapy with platinum-based regimens. Also used as a second-line therapy for treatment-sensitive small cell lung cancer, as well as in combination with cisplatin for the treatment of stage IV-B, recurrent, or persistent cervical cancer not amenable to curative treatment with surgery and/or radiation 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): Topotecan, a semi-synthetic derivative of camptothecin (a plant alkaloid obtained from the Camptotheca acuminata tree), is an anti-tumor drug with topoisomerase I-inhibitory activity similar to irinotecan. DNA topoisomerases are enzymes in the cell nucleus that regulate DNA topology (3-dimensional conformation) and facilitate nuclear processes such as DNA replication, recombination, and repair. During these processes, DNA topoisomerase I creates reversible single-stranded breaks in double-stranded DNA, allowing intact single DNA strands to pass through the break and relieve the topologic constraints inherent in supercoiled DNA. The 3'-DNA terminus of the broken DNA strand binds covalently with the topoisomerase enzyme to form a catalytic intermediate called a cleavable complex. After DNA is sufficiently relaxed and the strand passage reaction is complete, DNA topoisomerase reattaches the broken DNA strands to form the unaltered topoisomers that allow transcription to proceed. Topotecan interferes with the growth of cancer cells, which are eventually destroyed. Since the growth of normal cells can be affected by the medicine, other effects may also occur. Unlike irinotecan, topotecan is found predominantly in the inactive carboxylate form at neutral pH and it is not a prodrug. •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): Topotecan has the same mechanism of action as irinotecan and is believed to exert its cytotoxic effects during the S-phase of DNA synthesis. Topoisomerase I relieves torsional strain in DNA by inducing reversible single strand breaks. Topotecan binds to the topoisomerase I-DNA complex and prevents religation of these single strand breaks. This ternary complex interferes with the moving replication fork, which leads to the induction of replication arrest and lethal double-stranded breaks in DNA. As mammalian cells cannot efficiently repair these double strand breaks, the formation of this ternary complex eventually leads to apoptosis (programmed cell death). Topotecan mimics a DNA base pair and binds at the site of DNA cleavage by intercalating between the upstream (−1) and downstream (+1) base pairs. Intercalation displaces the downstream DNA, thus preventing religation of the cleaved strand. By specifically binding to the enzyme–substrate complex, Topotecan acts as an uncompetitive inhibitor. •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): 35% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Topotecan undergoes a reversible pH dependent hydrolysis of its lactone moiety; it is the lactone form that is pharmacologically active. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Renal clearance is an important determinant of topotecan elimination. In a mass balance/excretion study in 4 patients with solid tumors, the overall recovery of total topotecan and its N-desmethyl metabolite in urine and feces over 9 days averaged 73.4 ± 2.3% of the administered IV dose. Fecal elimination of total topotecan accounted for 9 ± 3.6% while fecal elimination of N-desmethyl topotecan was 1.7 ± 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): 2-3 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): 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 primary anticipated complication of overdosage would consist of bone marrow suppression. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Hycamtin •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Topotecan Topotecane Topotecanum •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): Topotecan is an antineoplastic agent used to treat ovarian cancer, small cell lung cancer, or cervical 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 Torasemide interact?

•Drug A: Adalimumab •Drug B: Torasemide •Severity: MODERATE •Description: The metabolism of Torasemide 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): Torasemide is indicated for the treatment of edema associated with congestive heart failure, renal or hepatic diseases. From this condition, it has been observed that torasemide is very effective in cases of kidney failure. As well, torasemide is approved to be used as an antihypertensive agent either alone or in combination with other antihypertensives. •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): It is widely known that administration of torasemide can attenuate renal injury and reduce the severity of acute renal failure. This effect is obtained by increasing urine output and hence, facilitating fluid, acid-base and potassium control. This effect is obtained by the increase in the excretion of urinary sodium and chloride. Several reports have indicated that torasemide presents a long-lasting diuresis and less potassium excretion which can be explained by the effect that torasemide has on the renin-angiotensin-aldosterone system. This effect is very similar to the effect observed with the administration of combination therapy with furosemide and spironolactone and it is characterized by a decrease in plasma brain natriuretic peptide and improved measurements of left ventricular function. Above the aforementioned effect, torasemide presents a dual effect.in which the inhibition of aldosterone which donates torasemide with a potassium-sparing action. Torasemide has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients suffering from chronic kidney disease. As well, some reports have indicated that torasemide can reduce myocardial fibrosis by reducing the collagen accumulation. This effect is suggested to be related to the decrease in aldosterone which in order has been shown to reduce the production of the enzyme procollagen type I carboxy-terminal proteinase which is known to be overexpressed in heart failure 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): As mentioned above, torasemide is part of the loop diuretics and thus, it acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by the binding of torasemide to a chloride ion-binding site of the transport molecule. Torasemide is known to have an effect in the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after the activation of angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1 and thromboxane A2 and a reduction on the aldosterone receptor binding. •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): Torasemide is the diuretic with the highest oral bioavailability even in advanced stages of chronic kidney disease. This bioavailability tends to be higher than 80% regardless of the patient condition. The maximal serum concentration is reported to be of 1 hour and the absorption parameters are not affected by its use concomitantly 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): The volume of distribution of torasemide is 0.2 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Torasemide is found to be highly bound to plasma proteins, representing over 99% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Torasemide is extensively metabolized in the liver and only 20% of the dose remains unchanged and it is recovered in the urine. Metabolized via the hepatic CYP2C8 and CYP2C9 mainly by reactions of hydroxylation, oxidation and reduction to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Torasemide is mainly hepatically processed and excreted in the feces from which about 70-80% of the administered dose is excreted by this pathway. On the other hand, about 20-30% of the administered dose is found 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 average half-life of torasemide 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 rate of torasemide is considerably reduced by the presence of renal disorders. •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 torasemide in the rat is 5 g/kg. When overdose occurs, there is a marked diuresis with the danger of loss of fluid and electrolytes which has been seen to lead to somnolence, confusion, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, hemoconcentration dehydration and circulatory collapse. This effects can include some gastrointestinal disturbances. There is no increase in tumor incidence with torasemide and it is proven to not be mutagenic, not fetotoxic or teratogenic. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Demadex, Soaanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Torasemida Torasemide Torasémide Torasemidum Torsemide •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): Torasemide is a diuretic used to treat hypertension and edema associated with heart failure, renal failure, or liver 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 CYP2C9 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Torasemide interact? Information: •Drug A: Adalimumab •Drug B: Torasemide •Severity: MODERATE •Description: The metabolism of Torasemide 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): Torasemide is indicated for the treatment of edema associated with congestive heart failure, renal or hepatic diseases. From this condition, it has been observed that torasemide is very effective in cases of kidney failure. As well, torasemide is approved to be used as an antihypertensive agent either alone or in combination with other antihypertensives. •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): It is widely known that administration of torasemide can attenuate renal injury and reduce the severity of acute renal failure. This effect is obtained by increasing urine output and hence, facilitating fluid, acid-base and potassium control. This effect is obtained by the increase in the excretion of urinary sodium and chloride. Several reports have indicated that torasemide presents a long-lasting diuresis and less potassium excretion which can be explained by the effect that torasemide has on the renin-angiotensin-aldosterone system. This effect is very similar to the effect observed with the administration of combination therapy with furosemide and spironolactone and it is characterized by a decrease in plasma brain natriuretic peptide and improved measurements of left ventricular function. Above the aforementioned effect, torasemide presents a dual effect.in which the inhibition of aldosterone which donates torasemide with a potassium-sparing action. Torasemide has been shown to reduce extracellular fluid volume and blood pressure in hypertensive patients suffering from chronic kidney disease. As well, some reports have indicated that torasemide can reduce myocardial fibrosis by reducing the collagen accumulation. This effect is suggested to be related to the decrease in aldosterone which in order has been shown to reduce the production of the enzyme procollagen type I carboxy-terminal proteinase which is known to be overexpressed in heart failure 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): As mentioned above, torasemide is part of the loop diuretics and thus, it acts by reducing the oxygen demand in the medullary thick ascending loop of Henle by inhibiting the Na+/K+/Cl- pump on the luminal cell membrane surface. This action is obtained by the binding of torasemide to a chloride ion-binding site of the transport molecule. Torasemide is known to have an effect in the renin-angiotensin-aldosterone system by inhibiting the downstream cascade after the activation of angiotensin II. This inhibition will produce a secondary effect marked by the reduction of the expression of aldosterone synthase, TGF-B1 and thromboxane A2 and a reduction on the aldosterone receptor binding. •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): Torasemide is the diuretic with the highest oral bioavailability even in advanced stages of chronic kidney disease. This bioavailability tends to be higher than 80% regardless of the patient condition. The maximal serum concentration is reported to be of 1 hour and the absorption parameters are not affected by its use concomitantly 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): The volume of distribution of torasemide is 0.2 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Torasemide is found to be highly bound to plasma proteins, representing over 99% of the administered dose. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Torasemide is extensively metabolized in the liver and only 20% of the dose remains unchanged and it is recovered in the urine. Metabolized via the hepatic CYP2C8 and CYP2C9 mainly by reactions of hydroxylation, oxidation and reduction to 5 metabolites. The major metabolite, M5, is pharmacologically inactive. There are 2 minor metabolites, M1, possessing one-tenth the activity of torasemide, and M3, equal in activity to torasemide. Overall, torasemide appears to account for 80% of the total diuretic activity, while metabolites M1 and M3 account for 9% and 11%, respectively. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Torasemide is mainly hepatically processed and excreted in the feces from which about 70-80% of the administered dose is excreted by this pathway. On the other hand, about 20-30% of the administered dose is found 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 average half-life of torasemide 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 rate of torasemide is considerably reduced by the presence of renal disorders. •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 torasemide in the rat is 5 g/kg. When overdose occurs, there is a marked diuresis with the danger of loss of fluid and electrolytes which has been seen to lead to somnolence, confusion, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, hemoconcentration dehydration and circulatory collapse. This effects can include some gastrointestinal disturbances. There is no increase in tumor incidence with torasemide and it is proven to not be mutagenic, not fetotoxic or teratogenic. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Demadex, Soaanz •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Torasemida Torasemide Torasémide Torasemidum Torsemide •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): Torasemide is a diuretic used to treat hypertension and edema associated with heart failure, renal failure, or liver 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 CYP2C9 substrates. The severity of the interaction is moderate.

Does Adalimumab and Toripalimab interact?

•Drug A: Adalimumab •Drug B: Toripalimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Toripalimab. •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): Toripalimab is indicated in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma (NPC). It is also indicated as a second-line monotherapy for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after platinum-containing 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): The exposure-response relationships and time course of pharmacodynamic response for toripalimab have not been fully characterized. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor 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): The binding of programmed death ligands 1 and 2 (PD-L1 and PD-L2) to the PD-1 receptor on T-cells results in the inhibition of T-cell proliferation and cytokine production - this pathway therefore plays a vital role in immune inhibition and self-tolerance. In some cancers, PD-1 ligands may be overexpressed and result in the inhibition of tumor surveillance. Toripalimab is a monoclonal antibody directed against the PD-1 receptor. It blocks the PD-L1/PD-1 pathway, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. •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): Steady-state concentrations of toripalimab were reached by week 7 when administered every two weeks. •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): At steady-state, the mean volume of distribution was 3.7 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): As with other therapeutic proteins, toripalimab is likely degraded via catabolic processes into 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): 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 mean terminal elimination half-life after one dose of toripalimab was 10 ± 1.5 days. The mean terminal elimination half-life of toripalimab at steady-state was 18 ± 9.4 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 mean clearance after one dose of toripalimab was 14.9 mL/h. The mean clearance of toripalimab at steady-state was 9.5 mL/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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Loqtorzi •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): Toripalimab is a PD-1 blocking monoclonal antibody used for the treatment of metastatic and recurrent nasopharyngeal carcinomas.

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 Toripalimab interact? Information: •Drug A: Adalimumab •Drug B: Toripalimab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Toripalimab. •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): Toripalimab is indicated in combination with cisplatin and gemcitabine for the first-line treatment of adult patients with metastatic or recurrent locally advanced nasopharyngeal carcinoma (NPC). It is also indicated as a second-line monotherapy for the treatment of adults with recurrent unresectable or metastatic NPC with disease progression on or after platinum-containing 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): The exposure-response relationships and time course of pharmacodynamic response for toripalimab have not been fully characterized. In syngeneic mouse tumor models, blocking PD-1 activity resulted in decreased tumor 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): The binding of programmed death ligands 1 and 2 (PD-L1 and PD-L2) to the PD-1 receptor on T-cells results in the inhibition of T-cell proliferation and cytokine production - this pathway therefore plays a vital role in immune inhibition and self-tolerance. In some cancers, PD-1 ligands may be overexpressed and result in the inhibition of tumor surveillance. Toripalimab is a monoclonal antibody directed against the PD-1 receptor. It blocks the PD-L1/PD-1 pathway, releasing PD-1 pathway-mediated inhibition of the immune response, including the anti-tumor immune response. •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): Steady-state concentrations of toripalimab were reached by week 7 when administered every two weeks. •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): At steady-state, the mean volume of distribution was 3.7 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): As with other therapeutic proteins, toripalimab is likely degraded via catabolic processes into 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): 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 mean terminal elimination half-life after one dose of toripalimab was 10 ± 1.5 days. The mean terminal elimination half-life of toripalimab at steady-state was 18 ± 9.4 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 mean clearance after one dose of toripalimab was 14.9 mL/h. The mean clearance of toripalimab at steady-state was 9.5 mL/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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Loqtorzi •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): Toripalimab is a PD-1 blocking monoclonal antibody used for the treatment of metastatic and recurrent nasopharyngeal carcinomas. 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 Trabectedin interact?

•Drug A: Adalimumab •Drug B: Trabectedin •Severity: MAJOR •Description: The metabolism of Trabectedin 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 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): Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors. •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): Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. •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): Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. •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): Administered intravenously. •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): 94 to 98% •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): 33-50 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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Yondelis •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): Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Trabectedin interact? Information: •Drug A: Adalimumab •Drug B: Trabectedin •Severity: MAJOR •Description: The metabolism of Trabectedin 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 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): Indicated for treatment of advanced soft tissue sarcoma in patients refractory to or unsuitable to receive anthracycline or ifosfamide chemotherapy in Europe, Russia and South Korea. Approved for orphan drug status by the U.S. FDA for treatment of soft tissue sarcomas and ovarian cancer. Investigated for use/treatment in cancer/tumors (unspecified), gastric cancer, ovarian cancer, pediatric indications, sarcoma, and solid tumors. •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): Two of the rings in the drug's structure allows it to covalently bind to the minor groove of DNA. The third ring protrudes from the DNA which lets it interact with nearby nuclear proteins. This has the additive effect of blocking cell division at the G2 phase. •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): Trabectedin interacts with the minor groove of DNA and alkylates guanine at the N2 position, which bends towards the major groove. In this manner, it is thought that the drug affects various transcription factors involved in cell proliferation, particularly via the transcription-coupled nucleotide excision repair system. Trabectedin blocks the cell cycle at the G2 phase, while cells at the G1 phase are most sensitive to the drug. It also inhibits overexpression of the multidrug resistance-1 gene (MDR-1) coding for the P-glycoprotein that is a major factor responsible for cells developing resistance to cancer drugs. The agent is also thought to interfere with the nucleotide excision repair pathways of cancer cells, suggesting that it could be effective in the treatment of many cancer types including melanoma and sarcoma, as well as lung, breast, ovarian, endometrial and prostate cancers; clinical evaluations are underway in these indications. •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): Administered intravenously. •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): 94 to 98% •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): 33-50 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): No toxicity available •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Yondelis •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): Trabectedin is an alkylating agent approved for the treatment of unresectable or metastatic soft tissue sarcoma (liposarcoma or leiomyosarcoma). 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Tralokinumab interact?

•Drug A: Adalimumab •Drug B: Tralokinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tralokinumab. •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): Tralokinumab is indicated in Canada, the US, and the EU for the treatment of moderate-to-severe atopic dermatitis in patients who are candidates for systemic therapy and are inadequately controlled with topical interventions. In Canada, tralokinumab is only approved for adults, while in the US and Europe, it is approved for use in patients 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): Tralokinumab exerts its therapeutic effects by inhibiting the inflammatory cytokine (IL-13) primarily responsible for the pathogenesis of atopic dermatitis. It is administered subcutaneously with a loading dose of 600mg followed by a maintenance dose of 300mg every two weeks. In clinical studies, tralokinumab treatment decreased the concentrations of a number of Th2 and Th22 immunity biomarkers in the blood, including periostin, IL-22, serum IgE. It also reduced epidermal thickness and decreased the expression of Keratin 16 and Ki-67 in skin affected by atopic dermatitis. Hypersensitivity reactions, including anaphylaxis, have been reported following the use of tralokinumab. Patients experiencing a systemic hypersensitivity reaction should discontinue treatment and initiate immediate therapy as clinically indicated. Tralokinumab should not be used in patients with pre-existing helminth infections, as the influence of tralokinumab on the immune response against helminth infections is unclear. Patients with helminth infections should be treated prior to therapy with tralokinumab. Patients becoming infected during the course of therapy may be treated with anti-helminth medications, but should discontinue tralokinumab if the infection fails to resolve. •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): Interleukin-13 (IL-13) is a pro-inflammatory cytokine that has been implicated as the primary driver of atopic dermatitis (AD). IL-13 binds with high affinity to both a heterodimeric form of IL-13Rα1 - complexed with IL-4Rα - and to IL-13Rα2, both of which are expressed on keratinocytes and fibroblasts. While IL-13Rα2 does not appear to act as a signal mediator, the binding of IL-13 to heterodimeric IL-4Rα and IL-13Rα1 activates downstream Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) pathways which proceed to activate various signal transducer and activator of transcription (STAT) pathways. STAT signalling induces the expression of periostin, an extracellular matrix protein which serves a number of physiological functions in addition to its pathogenic role in skin fibrosis and chronic allergic inflammation. IL-13 also appears to contribute to skin barrier dysfunction via an indirect downregulation of filaggrin (FLG), a structural protein essential for correct skin barrier functioning. Tralokinumab is a monoclonal antibody targeted against IL-13. It neutralizes the activity of IL-13 by blocking its interaction with both the IL-13Rα1/IL-4Rα receptor complex and IL-13Rα2 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 absolute bioavailability of tralokinumab following subcutaneous administration is 76%, with a median T max of 5-8 days. In clinical trials, steady-state serum concentrations were achieved by week 16 of treatment, with trough concentrations ranging from 98.0±41.1 mcg/mL to 101.4±42.7 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 volume of distribution of tralokinumab as estimated by population pharmacokinetic analysis was 4.2 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available for the protein binding of tralokinumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As with other therapeutic and endogenous proteins, the metabolism of tralokinumab is likely to occur via catabolism to smaller peptides and amino acids and has not been studied directly. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of tralokinumab occurs through a non-saturable proteolytic 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 tralokinumab is approximately 22 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 tralokinumab following subcutaneous administration was estimated to be 0.149 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): There are no data regarding overdosage with tralokinumab. In clinical trials, intravenous doses up to 30 mg/kg and subcutaneous doses of 600mg every two weeks for 3 months were found to be well-tolerated. In the event of a suspected overdose, patients should be administered supportive care as clinically indicated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Adbry •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): Tralokinumab is a monoclonal antibody directed against interleukin-13 which is used in the treatment of moderate-to-severe atopic dermatitis in patients requiring systemic therapy.

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 Tralokinumab interact? Information: •Drug A: Adalimumab •Drug B: Tralokinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tralokinumab. •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): Tralokinumab is indicated in Canada, the US, and the EU for the treatment of moderate-to-severe atopic dermatitis in patients who are candidates for systemic therapy and are inadequately controlled with topical interventions. In Canada, tralokinumab is only approved for adults, while in the US and Europe, it is approved for use in patients 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): Tralokinumab exerts its therapeutic effects by inhibiting the inflammatory cytokine (IL-13) primarily responsible for the pathogenesis of atopic dermatitis. It is administered subcutaneously with a loading dose of 600mg followed by a maintenance dose of 300mg every two weeks. In clinical studies, tralokinumab treatment decreased the concentrations of a number of Th2 and Th22 immunity biomarkers in the blood, including periostin, IL-22, serum IgE. It also reduced epidermal thickness and decreased the expression of Keratin 16 and Ki-67 in skin affected by atopic dermatitis. Hypersensitivity reactions, including anaphylaxis, have been reported following the use of tralokinumab. Patients experiencing a systemic hypersensitivity reaction should discontinue treatment and initiate immediate therapy as clinically indicated. Tralokinumab should not be used in patients with pre-existing helminth infections, as the influence of tralokinumab on the immune response against helminth infections is unclear. Patients with helminth infections should be treated prior to therapy with tralokinumab. Patients becoming infected during the course of therapy may be treated with anti-helminth medications, but should discontinue tralokinumab if the infection fails to resolve. •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): Interleukin-13 (IL-13) is a pro-inflammatory cytokine that has been implicated as the primary driver of atopic dermatitis (AD). IL-13 binds with high affinity to both a heterodimeric form of IL-13Rα1 - complexed with IL-4Rα - and to IL-13Rα2, both of which are expressed on keratinocytes and fibroblasts. While IL-13Rα2 does not appear to act as a signal mediator, the binding of IL-13 to heterodimeric IL-4Rα and IL-13Rα1 activates downstream Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2) pathways which proceed to activate various signal transducer and activator of transcription (STAT) pathways. STAT signalling induces the expression of periostin, an extracellular matrix protein which serves a number of physiological functions in addition to its pathogenic role in skin fibrosis and chronic allergic inflammation. IL-13 also appears to contribute to skin barrier dysfunction via an indirect downregulation of filaggrin (FLG), a structural protein essential for correct skin barrier functioning. Tralokinumab is a monoclonal antibody targeted against IL-13. It neutralizes the activity of IL-13 by blocking its interaction with both the IL-13Rα1/IL-4Rα receptor complex and IL-13Rα2 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 absolute bioavailability of tralokinumab following subcutaneous administration is 76%, with a median T max of 5-8 days. In clinical trials, steady-state serum concentrations were achieved by week 16 of treatment, with trough concentrations ranging from 98.0±41.1 mcg/mL to 101.4±42.7 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 volume of distribution of tralokinumab as estimated by population pharmacokinetic analysis was 4.2 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Little information is available for the protein binding of tralokinumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): As with other therapeutic and endogenous proteins, the metabolism of tralokinumab is likely to occur via catabolism to smaller peptides and amino acids and has not been studied directly. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): The elimination of tralokinumab occurs through a non-saturable proteolytic 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 tralokinumab is approximately 22 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 tralokinumab following subcutaneous administration was estimated to be 0.149 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): There are no data regarding overdosage with tralokinumab. In clinical trials, intravenous doses up to 30 mg/kg and subcutaneous doses of 600mg every two weeks for 3 months were found to be well-tolerated. In the event of a suspected overdose, patients should be administered supportive care as clinically indicated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Adbry •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): Tralokinumab is a monoclonal antibody directed against interleukin-13 which is used in the treatment of moderate-to-severe atopic dermatitis in patients requiring systemic therapy. 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 Tramadol interact?

•Drug A: Adalimumab •Drug B: Tramadol •Severity: MODERATE •Description: The metabolism of Tramadol 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): Tramadol is approved for the management of moderate to severe pain in adults. Tramadol is also used off-label in the treatment of premature ejaculation. •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): Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. Central Nervous System In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation. Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose. Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold. Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome. Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Endocrine System Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors. Cardiovascular Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol. QTc-Interval Prolongation The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point. Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose. Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug. Abuse and Misuse Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death. Therefore, tramadol should be prescribed and handled with caution. Dependence/Tolerance Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic 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. •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): Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine. Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor. In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages. •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 Administration Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability. Intramuscular Administration Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. Rectal Administration Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to 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): The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL. Saturation only occurs at concentrations outside of the clinical range. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme. CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41. Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1. There are also large differences in the frequency of these alleles between different ethnicities: *3, *4, *5, *6, and *41 are more common among Caucasians while *17 is more common in Africans for example. Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol. Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1). The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing. •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): Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 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 clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults. •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 LD50 for tramadol, when administered orally in mice, is 350 mg/kg. In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Conzip, Durela, Qdolo, Ralivia, Ryzolt, Seglentis, Tridural, Ultracet, Ultram, Zytram •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): Tramadol is a centrally-acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain 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 CYP2B6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Tramadol interact? Information: •Drug A: Adalimumab •Drug B: Tramadol •Severity: MODERATE •Description: The metabolism of Tramadol 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): Tramadol is approved for the management of moderate to severe pain in adults. Tramadol is also used off-label in the treatment of premature ejaculation. •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): Tramadol modulates the descending pain pathways within the central nervous system through the binding of parent and M1 metabolite to μ-opioid receptors and the weak inhibition of the reuptake of norepinephrine and serotonin. Apart from analgesia, tramadol may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. Central Nervous System In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed. Tramadol produces respiratory depression by direct action on brain stem respiratory centres. The respiratory depression involves both a reduction in the responsiveness of the brain stem centres to increases in CO2 tension and to electrical stimulation. Tramadol depresses the cough reflex by a direct effect on the cough centre in the medulla. Antitussive effects may occur with doses lower than those usually required for analgesia. Tramadol causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomonic (e.g., pontine lesions of hemorrhagic or ischemic origin may produce similar findings). Marked mydriasis rather than miosis may be seen with hypoxia in the setting of oxycodone overdose. Seizures have been reported in patients receiving tramadol within the recommended dosage range. Spontaneous post-marketing reports indicate that seizure risk is increased with doses of tramadol above the recommended range. Risk of convulsions may also increase in patients with epilepsy, those with a history of seizures or in patients with a recognized risk for seizure (such as head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections), or with concomitant use of other drugs known to reduce the seizure threshold. Tramadol can cause a rare but potentially life-threatening condition resulting from concomitant administration of serotonergic drugs (e.g., anti-depressants, migraine medications). Treatment with the serotoninergic drug should be discontinued if such events (characterized by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Tramadol should not be used in combination with MAO inhibitors or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in combination with other serotonergic drugs (triptans, certain tricyclic antidepressants, lithium, St. John’s Wort) due to the risk of serotonin syndrome. Gastrointestinal Tract and Other Smooth Muscle Tramadol causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm resulting in constipation. Other opioid-induced effects may include a reduction in gastric, biliary and pancreatic secretions, spasm of the sphincter of Oddi, and transient elevations in serum amylase. Endocrine System Opioids may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin and decreases in plasma cortisol and testosterone. Clinical signs and symptoms may be manifest from these hormonal changes. Hyponatremia has been reported very rarely with the use of tramadol, usually in patients with predisposing risk factors, such as elderly patients and/or patients using concomitant medications that may cause hyponatremia (e.g., antidepressants, benzodiazepines, diuretics). In some reports, hyponatremia appeared to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and resolved with discontinuation of tramadol and appropriate treatment (e.g., fluid restriction). During tramadol treatment, monitoring for signs and symptoms of hyponatremia is recommended for patients with predisposing risk factors. Cardiovascular Tramadol administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of drugs such as phenothiazines and other tranquillizers, sedative/hypnotics, tricyclic antidepressants or general anesthetics. These patients should be monitored for signs of hypotension after initiating or titrating the dose of tramadol. QTc-Interval Prolongation The maximum placebo-adjusted mean change from baseline in the QTcF interval was 5.5 ms in the 400 mg/day treatment arm and 6.5 ms in the 600 mg/day mg treatment arm, both occurring at the 8h time point. Both treatment groups were within the 10 ms threshold for QT prolongation. Post-marketing experience with the use of tramadol containing products included rare reports of QT prolongation reported with an overdose. Particular care should be exercised when administering tramadol to patients who are suspected to be at an increased risk of experiencing torsade de pointes during treatment with a QTc-prolonging drug. Abuse and Misuse Like all opioids, tramadol has the potential for abuse and misuse, which can lead to overdose and death. Therefore, tramadol should be prescribed and handled with caution. Dependence/Tolerance Physical dependence and tolerance reflect the neuroadaptation of the opioid receptors to chronic exposure to an opioid and are separate and distinct from abuse and addiction. Tolerance, as well as physical dependence, may develop upon repeated administration of opioids, and are not by themselves evidence of an addictive disorder or abuse. Patients on prolonged therapy should be tapered gradually from the drug if it is no longer required for pain control. Withdrawal symptoms may occur following abrupt discontinuation of therapy or upon administration of an opioid antagonist. Some of the symptoms that may be associated with abrupt withdrawal of an opioid analgesic 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. •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): Tramadol is a centrally acting μ-opioid receptor agonist and SNRI (serotonin/norepinephrine reuptake-inhibitor) that is structurally related to codeine and morphine. Tramadol binds weakly to κ- and δ-opioid receptors and to the μ-opioid receptor with 6000-fold less affinity than morphine. Tramadol exists as a racemic mixture consisting of two pharmacologically active enantiomers that both contribute to its analgesic property through different mechanisms: (+)-tramadol and its primary metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the μ opioid receptor while (+)-tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake. These pathways are complementary and synergistic, improving tramadol's ability to modulate the perception of and response to pain. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol has also been shown to affect a number of pain modulators including alpha2-adrenoreceptors, neurokinin 1 receptors, the voltage-gated sodium channel type II alpha subunit, transient receptor potential cation channel subfamily V member 1 (TRPV1 - also known as the capsaicin receptor), muscarinic receptors (M1 and M3), N-methyl-D-aspartate receptor (also known as the NMDA receptor or glutamate receptor), Adenosine A1 receptors, and nicotinic acetylcholine receptor. In addition to the above neuronal targets, tramadol has a number of effects on inflammatory and immune mediators involved in the pain response. This includes inhibitory effects on cytokines, prostaglandin E2 (PGE2), nuclear factor-κB, and glial cells as well as a change in the polarization state of M1 macrophages. •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 Administration Tramadol is administered as a racemate, with both the [-] and [+] forms of both tramadol and the M1 metabolite detected in circulation. Following administration, racemic tramadol is rapidly and almost completely absorbed, with a bioavailability of 75%. This difference in absorption and bioavailability can be attributed to the 20-30% first-pass metabolism. Peak plasma concentrations of tramadol and the primary metabolite M1 occur at two and three hours, respectively. Following a single oral dose of 100mg of tramadol, the Cmax was found to be approximately 300μg/L with a Tmax of 1.6-1.9 hours, while metabolite M1 was found to have a Cmax of 55μg/L with a Tmax of 3 hours. Steady-state plasma concentrations of both tramadol and M1 are achieved within two days of dosing. There is no evidence of self-induction. Following multiple oral doses, Cmax is 16% higher and AUC is 36% higher than after a single dose, demonstrating a potential role of saturable first-pass hepatic metabolism in increasing bioavailability. Intramuscular Administration Tramadol is rapidly and almost completely absorbed following intramuscular administration. Following injection of 50mg of tramadol, Cmax of 166μg/L was found with a Tmax of 0.75 hours. Rectal Administration Following rectal administration with suppositories containing 100mg of tramadol, Cmax of 294μg/L was found with a Tmax of 3.3 hours. The absolute bioavailability was found to be higher than oral administration (77% vs 75%), likely due to reduced first-pass metabolism with rectal administration compared to 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): The volume of distribution of tramadol is reported to be in the range of 2.6-2.9 L/kg. Tramadol has high tissue affinity; the total volume of distribution after oral administration was 306L and 203L after parenteral administration. Tramadol crosses the blood-brain barrier with peak brain concentrations occurring 10 minutes following oral administration. It also crosses the placental barrier with umbilical concentrations being found to be ~80% of maternal concentrations. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): About 20% of the administered dose is found to bind to plasma proteins. Protein binding appears to be independent of concentrations up to 10μg/mL. Saturation only occurs at concentrations outside of the clinical range. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tramadol undergoes extensive first-pass metabolism in the liver by N- and O- demethylation and conjugation. From the extensive metabolism, there have been identified at least 23 metabolites. There are two main metabolic pathways: the O-demethylation of tramadol to produce O-desmethyl-tramadol (M1) catalyzed by CYP2D6 and the N-demethylation to N-desmethyl-tramadol (M2) catalyzed by CYP3A4 and CYP2B6. The wide variability in the pharmacokinetic properties between patients can partly be ascribed to polymorphisms within the gene for CYP2D6 that determine its enzymatic activity. CYP2D6*1 is considered the wild-type allele associated with normal enzyme activity and the "extensive metabolizer" phenotype; 90-95% of Caucasians are considered "extensive metabolizers" (with normal CYP2D6 function) while the remaining 5-10% are considered "poor metabolizers" with reduced or non-functioning enzyme. CYP2D6 alleles associated with non-functioning enzyme include *3, *4, *5, and *6 while alleles associated with reduced activity include *9, *10, *17, and *41. Poor metabolizers have reduced activity of the CYP2D6 enzyme and therefore less production of tramadol metabolites M1 and M2, which ultimately results in a reduced analgesic effect as tramadol interacts with the μ-opioid receptor primarily via M1. There are also large differences in the frequency of these alleles between different ethnicities: *3, *4, *5, *6, and *41 are more common among Caucasians while *17 is more common in Africans for example. Compared to 5-10% of Caucasians, only ~1% of Asians are considered poor metabolizers, however Asian populations carry a much higher frequency (51%) of the CYP2D6*10 allele, which is relatively rare in Caucasian populations and results in higher exposure to tramadol. Some individuals are considered "ultra-rapid metabolizers", such as those carrying CYP2D6 gene duplications (CYP2D6*DUP) or multiplications. These individuals are at risk of intoxication or exaggerated effects of tramadol due to higher concentrations of its active metabolite (M1). The occurrence of this phenotype is seen in approximately 1% to 2% of East Asians (Chinese, Japanese, Korean), 1% to 10% of Caucasians, 3% to 4% of African-Americans, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jews, Puerto Rican). The FDA label recommends avoiding the use of tramadol in these individuals. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tramadol is eliminated primarily through metabolism by the liver and the metabolites are excreted primarily by the kidneys, accounting for 90% of the excretion while the remaining 10% is excreted through feces. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing. •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): Tramadol reported a half-life of 5-6 hours while the M1 metabolite presents a half-life of 8 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 clinical trials, the clearance rate of tramadol ranged from 3.73 ml/min/kg in renal impairment patients to 8.50 ml/min/kg in healthy adults. •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 LD50 for tramadol, when administered orally in mice, is 350 mg/kg. In carcinogenic studies, there are reports of murine tumors which cannot be concluded to be carcinogenic in humans. On the other hand, tramadol showed no evidence to be mutagenic in different assays and does not have effects on fertility. However, there are clear reports of embryotoxicity and fetotoxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Conzip, Durela, Qdolo, Ralivia, Ryzolt, Seglentis, Tridural, Ultracet, Ultram, Zytram •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): Tramadol is a centrally-acting opioid agonist and SNRI (serotonin/norepinephrine reuptake inhibitor) used for the management of moderate to severe pain 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 CYP2B6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Trastuzumab deruxtecan interact?

•Drug A: Adalimumab •Drug B: Trastuzumab deruxtecan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Trastuzumab deruxtecan. •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): In the US, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. In Canada, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously been treated with trastuzumab emtansine, or who have received at least one prior anti-HER2-based regimen either in the metastatic setting or in the adjuvant/neoadjuvant setting who have experienced disease recurrence during or within 6 months of adjuvant/neoadjuvant therapy. Trastuzumab deruxtecan is also indicated in Canada for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. In Europe, trastuzumab deruxtecan is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens and unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. It is also indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. It is also indicated as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer whose tumors have an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy. •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): Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy. By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors. The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug. •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): Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor. It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes. Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase. •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 Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%). •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 volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study. Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The Dxd portion of the drug has a plasma protein binding estimated at 97%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG. Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody. In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces. Unmetabolized DXd was found in the urine during a pharmacokinetic study. •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 pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 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): Trastuzumab deruxtecan is rapidly cleared from systemic circulation. Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 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): LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Enhertu •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): Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast 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 Trastuzumab deruxtecan interact? Information: •Drug A: Adalimumab •Drug B: Trastuzumab deruxtecan •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Trastuzumab deruxtecan. •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): In the US, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy. It is also indicated to treat adults with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. Trastuzumab deruxtecan is also indicated to treat adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen. In Canada, trastuzumab deruxtecan is indicated for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously been treated with trastuzumab emtansine, or who have received at least one prior anti-HER2-based regimen either in the metastatic setting or in the adjuvant/neoadjuvant setting who have experienced disease recurrence during or within 6 months of adjuvant/neoadjuvant therapy. Trastuzumab deruxtecan is also indicated in Canada for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer who have received at least one prior line of chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. In Europe, trastuzumab deruxtecan is indicated as monotherapy for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received one or more prior anti-HER2-based regimens and unresectable or metastatic HER2-low breast cancer who have received prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. It is also indicated for the treatment of adult patients with advanced HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. It is also indicated as a monotherapy for the treatment of adult patients with advanced non-small cell lung cancer whose tumors have an activating HER2 mutation and who require systemic therapy following platinum-based chemotherapy with or without immunotherapy. •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): Trastuzumab demonstrates antitumor activity against certain types of HER2 positive breast cancer, however, clinical trials are still ongoing to confirm its efficacy. By exploiting both targeted antibody and cytotoxic effects, trastuzumab deruxtecan can effectively destroy tumors. The FDA label warns of a potential risk for neutropenia, interstitial lung disease/pneumonitis, and left ventricular dysfunction following the use of this drug. •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): Trastuzumab deruxtecan is a humanized anti-HER2 IgG1 antibody, targeting cancer cause by mutation of the HER2 gene. In addition, the small molecule portion of this drug, deruxtecan (DXd), is a topoisomerase I inhibitor. It is attached to the antibody by a peptide linker. After trastuzumab deruxtecan binds to HER2 found on malignant cells, it is internalized and linker cleavage occurs through the actions of lysosomal enzymes. After it is released through cleavage, DXd causes targeted DNA damage and apoptosis in cancer cells, due to the ability to cross cell membranes. Normally, drugs in this class (antibody-drug conjugates) present a challenge. The monoclonal antibody accurately targets cancer cells, however exert limited killing action. The addition of a cytotoxic agent (a topoisomerase I inhibitor in this case) effectively kills dividing cancer cells, including those in the healthy tissues, leading to various adverse effects. The peptide linker used to formulate this drug is cleavable, which is unique to other antibody-drug conjugates, allowing for increased efficacy and reduced drug resistance to topoisomerase. •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 Cmax of trastuzumab deruxtecan at normal therapeutic doses was 122 μg/mL (20%). The AUC of trastuzumab deruxtecan was 735 μg·day/mL (31%). •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 volume of distribution of trastuzumab deruxtecan in the central compartment is 2.77 L, according to a population based pharmacokinetic study. Pharmacokinetic studies found that the unchanged drug is distributed in the blood and is not significantly retained in tissues. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The Dxd portion of the drug has a plasma protein binding estimated at 97%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trastuzumab deruxtecan is likely broken down into small peptides and amino acids through catabolism, just as the metabolism of endogenous IgG. Cathepsin B and L enzymes are thought to be involved in the cleavage of the peptide linker that joins the topoisomerase I inhibitor and the antibody. In vitro, DXd, the topoisomerase inhibitor portion of the drug, is found to be metabolized by CYP3A4. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): A pharmacokinetic study revealed that this drug was mainly excreted in the feces. Another study determined that 67% of a dose was excreted in the feces. Unmetabolized DXd was found in the urine during a pharmacokinetic study. •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 pharmacokinetic study, the median elimination half-life of trastuzumab deruxtecan was about 5.8 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): Trastuzumab deruxtecan is rapidly cleared from systemic circulation. Estimated systemic clearance of trastuzumab deruxtecan is 0.42 L/day, according to a population pharmacokinetic analysis. DXd showed a systemic clearance of about 19.2 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): LD50 and overdose information are not currently available, but effects of an overdose are likely to impact the lungs, heart, and circulatory system, leading to significant toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Enhertu •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): Trastuzumab deruxtecan is an antibody used to treat certain types of unresectable or metastatic HER2 positive breast 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 Trastuzumab emtansine interact?

•Drug A: Adalimumab •Drug B: Trastuzumab emtansine •Severity: MAJOR •Description: The metabolism of Trastuzumab emtansine 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): Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. •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): Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis. •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): Trastuzumab emtansine is a HER2 antibody-drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis. Trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by trastuzumab emtansine. •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/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV. •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 trastuzumab emtansine is about 3.13 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): DM1 has a plasma protein binding value of 93%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes. •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 has not yet been fully elucidated. •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): Trastuzumab emtansine has a long half life of about 4 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): After IV infusion, trastuzumab emtansine has a clearance of 0.68 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): The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Kadcyla •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): Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Trastuzumab emtansine interact? Information: •Drug A: Adalimumab •Drug B: Trastuzumab emtansine •Severity: MAJOR •Description: The metabolism of Trastuzumab emtansine 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): Used in HER2-positive, metastatic breast cancer patients who have already used taxane and/or trastuzumab for metastatic disease or had their cancer recur within 6 months of adjuvant treatment. •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): Trastuzumab emtansine was evaluated in two Herceptin-responsive and one Herceptin-resistant breast tumor models. In the Herceptin-responsive models, Trastuzumab-DM1 caused complete tumor regression in all mice, whereas Herceptin alone slowed tumor growth. In the Herceptin- resistant model, Herceptin alone had no effect on tumor growth. In contrast, Trastuzumab-DM1 caused >90% tumor reduction in all mice. In this Herceptin- resistant model, tumor regrowth was observed after cessation of Trastuzumab- DM1 treatment, yet regression re-occurred when dosing was resumed. The effect was specific for HER2-positive tumors. Thus the physiological effects of trastuzumab emtansine are cell cycle arrest and cell death by apoptosis. •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): Trastuzumab emtansine is a HER2 antibody-drug conjugate. The antibody portion is trastuzumab, which is humanized anti-HER2 IgG1, and produced in the mammalian Chinese Hamster Ovary cells. The drug portion is DM1, which is a maytansine derivative that inhibits microtubules. These two portions are covalently connected by 4-[N-maleimidomethyl] cyclohexane-1-carboxylate (MCC), which is a stable thioether linker. Together MCC and DM1 are called emtansine and are produced by chemical synthesis. Trastuzumab emtansine binds to the HER2 receptor’s sub-domain IV and goes into the cell by receptor-mediated endocytosis. Lysosomes degrade trastuzumab emtansine and release DM1. DM1 binds to tubulin in microtubules and inhibits microtubule function producing cell arrest and apoptosis. As well, similar to trastuzumab, in vitro studies have shown that both HER2 receptor signalling inhibition and antibody-dependent cytotoxicity are mediated by trastuzumab emtansine. •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/ bioavailability should be close to 100% since trastuzumab emtansine is administered IV. •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 trastuzumab emtansine is about 3.13 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): DM1 has a plasma protein binding value of 93%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trastuzumab emtansine undergoes lysosomal degradation to MCC-DM1, Lys-MCC-DM1, and DM1. All of these products are detected at low levels in the plasma. DM1 undergoes further degradation by CYP3A4 and CYP3A5, but DM1 does not induce or inhibit any of the CYP450 enzymes. •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 has not yet been fully elucidated. •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): Trastuzumab emtansine has a long half life of about 4 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): After IV infusion, trastuzumab emtansine has a clearance of 0.68 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): The FDA label includes a black box warning of serious side effects such as hepatotoxicity, embryo-fetal toxicity, and cardiac toxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Kadcyla •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): Trastuzumab emtansine is an antineoplastic agent and antibody-drug conjugate used to treat HER2-overexpressing 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Trastuzumab interact?

•Drug A: Adalimumab •Drug B: Trastuzumab •Severity: MODERATE •Description: The risk or severity of neutropenia can be increased when Trastuzumab is combined with Adalimumab. •Extended Description: While trastuzumab treatment itself can cause neutropenia, its co-administration with other immunosuppressive agents has been shown to result in synergistic neutropenic effects. In randomized controlled clinical trials, patients receiving trastuzumab in combination with myelosuppressive chemotherapy had higher rates of moderate to severe neutropenia and febrile neutropenia compared to those receiving chemotherapy alone. The pathophysiologic basis for this exacerbation of neutropenia has not been determined. •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 adjuvant treatment of HER2-overexpressing breast cancer, trastuzumab is indicated in several clinical settings: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as monotherapy following multi-modality anthracycline-based therapy. Trastuzumab is indicated as a first-line treatment, in combination with paclitaxel, for metastatic HER2-overexpressing breast cancer, and as monotherapy in patients who have previously received one or more chemotherapy regimens in the metastatic setting. In Europe, trastuzumab can also be used in combination with paclitaxel or docetaxel for the treatment of metastatic HER2-positive breast cancer in adult patients and with an aromatase inhibitor in postmenopausal patients. For HER2-positive early breast cancer, the EMA approved trastuzumab as monotherapy following surgery, chemotherapy (neoadjuvant or adjuvant), and radiation or following adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel. It can also be used in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin or with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy for locally advanced (including inflammatory) disease or tumors > 2 cm in diameter. Trastuzumab is also indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease by the FDA and EMA. Trastuzumab is indicated for subcutaneous administration - in combination with either hyaluronidase or both hyaluronidase and pertuzumab - for the treatment of adults with HER2-positive breast cancers. •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): Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells in vivo. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration. •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): Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation, and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction. Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor. •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): Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 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): 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): After it binds to HER2, trastuzumab is metabolized intracellularly into 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): Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very 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 terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, 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 predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 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): There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Herceptin, Herceptin Hylecta, Herzuma, Kanjinti, Ontruzant, Perjeta-Herceptin, Phesgo, Trazimera •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): Trastuzumab is a monoclonal anti-human epidermal growth factor receptor 2 protein antibody used to treat HER2-positive breast, gastroesophageal, and gastric cancers.

While trastuzumab treatment itself can cause neutropenia, its co-administration with other immunosuppressive agents has been shown to result in synergistic neutropenic effects. In randomized controlled clinical trials, patients receiving trastuzumab in combination with myelosuppressive chemotherapy had higher rates of moderate to severe neutropenia and febrile neutropenia compared to those receiving chemotherapy alone. The pathophysiologic basis for this exacerbation of neutropenia has not been determined. The severity of the interaction is moderate.

Question: Does Adalimumab and Trastuzumab interact? Information: •Drug A: Adalimumab •Drug B: Trastuzumab •Severity: MODERATE •Description: The risk or severity of neutropenia can be increased when Trastuzumab is combined with Adalimumab. •Extended Description: While trastuzumab treatment itself can cause neutropenia, its co-administration with other immunosuppressive agents has been shown to result in synergistic neutropenic effects. In randomized controlled clinical trials, patients receiving trastuzumab in combination with myelosuppressive chemotherapy had higher rates of moderate to severe neutropenia and febrile neutropenia compared to those receiving chemotherapy alone. The pathophysiologic basis for this exacerbation of neutropenia has not been determined. •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 adjuvant treatment of HER2-overexpressing breast cancer, trastuzumab is indicated in several clinical settings: as part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; as part of a treatment regimen with docetaxel and carboplatin; or as monotherapy following multi-modality anthracycline-based therapy. Trastuzumab is indicated as a first-line treatment, in combination with paclitaxel, for metastatic HER2-overexpressing breast cancer, and as monotherapy in patients who have previously received one or more chemotherapy regimens in the metastatic setting. In Europe, trastuzumab can also be used in combination with paclitaxel or docetaxel for the treatment of metastatic HER2-positive breast cancer in adult patients and with an aromatase inhibitor in postmenopausal patients. For HER2-positive early breast cancer, the EMA approved trastuzumab as monotherapy following surgery, chemotherapy (neoadjuvant or adjuvant), and radiation or following adjuvant chemotherapy with doxorubicin and cyclophosphamide in combination with paclitaxel or docetaxel. It can also be used in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin or with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy for locally advanced (including inflammatory) disease or tumors > 2 cm in diameter. Trastuzumab is also indicated, in combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease by the FDA and EMA. Trastuzumab is indicated for subcutaneous administration - in combination with either hyaluronidase or both hyaluronidase and pertuzumab - for the treatment of adults with HER2-positive breast cancers. •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): Trastuzumab exerts an antitumour activity and is used in the treatment of HER2-positive breast cancer. HER2 protein overexpression is observed in 20%-30% of primary breast cancers thus HER2 presents as a useful therapeutic target for the treatment of breast cancers. Trastuzumab has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumour cells that overexpress HER2. It works as a mediator of antibody-dependent cellular cytotoxicity, where it binds as an antibody to cells over-expressing HER2, leading to preferential cell death. Trastuzumab was also shown to inhibit angiogenesis of tumor cells in vivo. Higher doses and longer dosing intervals show no significant benefit over standard dose schedules. In patients with HER2 positive solid tumours, trastuzumab did not exert any clinically significant QTc interval duration. •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): Trastuzumab is a recombinant humanized IgG1 monoclonal antibody against the HER-2 receptor, a member of the epidermal growth factor receptors which is a photo-oncogene. Over-expressed in breast tumour cells, HER-2 overamplifies the signal provided by other receptors of the HER family by forming heterodimers. The HER-2 receptor is a transmembrane tyrosine kinase receptor that consists of an extracellular ligand-binding domain, a transmembrane region, and an intracellular or cytoplasmic tyrosine kinase domain. It is activated by the formation of homodimers or heterodimers with other EGFR proteins, leading to dimerization and autophosphorylation and/or transphosphorylation of specific tyrosine residues in EGFR intracellular domains. Further downstream molecular signaling cascades are activated, such as the Ras/Raf/mitogen-activated protein kinase (MAPK), the phosphoinositide 3-kinase/Akt, and the phospholipase Cγ (PLCγ)/protein kinase C (PKC) pathways that promote cell growth and survival and cell cycle progression. Due to upregulation of HER-2 in tumour cells, hyperactivation of these signaling pathways and abnormal cell proliferation is observed. Trastuzumab binds to the extracellular ligand-binding domain and blocks the cleavage of the extracellular domain of HER-2 to induce its antibody-induced receptor downmodulation, and subsequently inhibits HER-2-mediated intracellular signaling cascades. Inhibition of MAPK and PI3K/Akt pathways lead to an increase in cell cycle arrest, and the suppression of cell growth and proliferation. Trastuzumab also mediates the activation of antibody-dependent cell-mediated cytotoxicity (ADCC) by attracting the immune cells, such as natural killer (NK) cells, to tumor sites that overexpress HER-2. While the drug alone has a minimal potential to induce complement-dependent cytotoxicity (CDC), one study demonstrated increased therapeutic effectiveness and a synergistic effect on uterine serous carcinoma cells in vitro when used in combination with pertuzumab, which also has minor effects on CDC alone. This study showed that only the combination of both cell-bound antibodies would be sufficient to bind and activate the complement component 1q (C1q) required to initiate the complement cascade reaction. Intrinsic trastuzumab resistance has been noted for some patients with HER-2 positive breast cancer. Mechanisms involving trastuzumab resistance include deficiency of phosphatase and tensin homologue and activation of phosphoinositide 3-kinase, and the overexpression of other surface receptors, such as insulin-like growth factor. •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): Peak and trough plasma concentrations at steady state (between weeks 16 and 32) were approximately 123 and 79 mcg/mL, respectively. At the highest weekly dose studied (500 mg), mean peak serum concentration was 377 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): 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): After it binds to HER2, trastuzumab is metabolized intracellularly into 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): Following metabolism, the complex elimination of trastuzumab in humans is mediated by epithelial cells in a dose-dependent (nonlinear) fashion. The renal excretion of trastuzumab is very 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 terminal half-life is approximately 28 days, but may decrease with lower doses - at the 10mg and 500mg doses, half-lives averaged approximately 1.7 and 12 days, 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 predicted steady-state clearance of trastuzumab is 0.173 - 0.337 L/day, dependent primarily on the dosing regimen. The clearance rate for subcutaneously administered trastuzumab, formulated with hyaluronidase for improved subcutaneous absorption, is 0.11 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): There is no experience with overdosage of trastuzumab in clinical trials - single doses >8 mg/kg have not been tested in humans. Trastuzumab can contribute to the development of ventricular dysfunction and congestive heart failure, particularly when used in combination (or temporally adjacent) to other cardiotoxic chemotherapies such as anthracyclines. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Herceptin, Herceptin Hylecta, Herzuma, Kanjinti, Ontruzant, Perjeta-Herceptin, Phesgo, Trazimera •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): Trastuzumab is a monoclonal anti-human epidermal growth factor receptor 2 protein antibody used to treat HER2-positive breast, gastroesophageal, and gastric cancers. Output: While trastuzumab treatment itself can cause neutropenia, its co-administration with other immunosuppressive agents has been shown to result in synergistic neutropenic effects. In randomized controlled clinical trials, patients receiving trastuzumab in combination with myelosuppressive chemotherapy had higher rates of moderate to severe neutropenia and febrile neutropenia compared to those receiving chemotherapy alone. The pathophysiologic basis for this exacerbation of neutropenia has not been determined. The severity of the interaction is moderate.

Does Adalimumab and Trazodone interact?

•Drug A: Adalimumab •Drug B: Trazodone •Severity: MODERATE •Description: The metabolism of Trazodone 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): Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors. •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): Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected. •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 trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms. •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): Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%. •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): A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of trazodone is 89-95% according to in vitro studies. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid. •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 an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine 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): The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 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): A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone. •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 trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Desyrel, Oleptro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trazodona Trazodone Trazodonum •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): Trazodone is a serotonin uptake inhibitor used to treat major depressive 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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Trazodone interact? Information: •Drug A: Adalimumab •Drug B: Trazodone •Severity: MODERATE •Description: The metabolism of Trazodone 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): Trazodone is indicated for the treatment of major depressive disorder (MDD). It has been used off-label for adjunct therapy in alcohol dependence, and off-label to treat anxiety and insomnia. It may also be used off-label to treat symptoms of dementia, Alzheimer’s disease, schizophrenia, eating disorders, and fibromyalgia due to its effects on various neurotransmitter receptors. •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): Trazodone treats depressed mood and other depression-related symptoms and shows benefit in the treatment of insomnia due to its sedating effects. It is known to prolong the cardiac QT-interval. Memory, alertness, and cognition may be decreased by trazodone, especially in elderly patients due to its central nervous system depressant effects. A note on priapism Trazodone has been associated with the occurrence of priapism, a painful and persistent incidence of penile tissue erection that is unrelievable and can cause permanent neurological damage if left untreated. Patients must be advised to seek immediate medical attention if priapism is suspected. •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 trazodone is not fully understood, however, it is known to inhibit the reuptake of serotonin and block both histamine and alpha-1-adrenergic receptors. Despite the fact that trazodone is frequently considered a selective serotonin reuptake inhibitor, several reports have shown that other mechanisms including antagonism at serotonin 5-HT1a, 5-HT1c, and 5-HT2 receptor subtypes may occur. The strongest antagonism of trazodone is reported to occur at the serotonin 5-HT21c receptors, preventing serotonin uptake. In addition to acting on serotonin receptors, trazodone has been shown to inhibit serotonin transporters. The antidepressant effects of trazodone result from the inhibition of receptor uptake, which normally decreases circulating neurotransmitters, contributing to depressive symptoms. •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): Trazodone is rapidly absorbed in the gastrointestinal tract after oral administration, with a bioavailability ranging from 63-91% and an AUC0−t of 18193.0 ng·h/mL. Food may impact absorption in a variable fashion, and may sometimes lead to decreases in the Cmax of trazodone. In the fed state in 8 healthy volunteers, the Cmax was measured to be 1.47 +/- 0.16 micrograms/mL, and in the fasted state, was measured at 1.88 +/- 0.42 micrograms/mL. The average Tmax after a single dose of 300 mg was 8 hours. Food may increase absorption by up to 20%. •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): A single-dose pharmacokinetic study of 8 volunteers taking trazodone determined a volume of distribution of 0.84 +/- 0.16 L/kg. The FDA medical review of trazodone reports a volume of distribution of 0.47 to 0.84 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of trazodone is 89-95% according to in vitro studies. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trazodone is heavily metabolized and activated in the liver by CYP3A4 enzyme to the active metabolite, m-chlorophenylpiperazine (mCPP). The full metabolism of trazodone has not been well characterized. Some other metabolites that have been identified are a dihydrodiol metabolite and carboxylic acid. •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 an oral dose is excreted unchanged in the urine. In a pharmacokinetic study, about 60-70% of radiolabeled was excreted urine within 48 hours. Approximately 9-29% was found to be excreted in feces over a range of 60 to 100 hours. According to the FDA medical review, the kidneys are responsible for 70 to 75% of trazodone excretion. About 21% of trazodone is reported to be excreted by the fecal route and 0.13% of the parent drug is eliminated in the urine 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): The plasma elimination half-life was markedly prolonged (13.6 versus 6 hours) elderly volunteers in the fasted state when compared with younger volunteers. Another study of 8 healthy individuals taking a single dose of trazodone indicated a terminal elimination half-life of 7.3 +/- 0.8 hr. A two-phase pattern of trazodone elimination has been reported. Initially, the half-life is reported to range from 3 to 6 hours and the second phase of elimination to range from 5 to 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): A decrease in total apparent clearance (5.1 versus 10.8 L/h) was seen elderly volunteers in the fasted state when compared with younger volunteers. Another pharmacokinetic study determined the total body clearance of trazodone to be 5.3 +/- 0.9 L/hr in 8 healthy patients taking a single dose of trazodone. •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 trazodone is 690 mg/kg in rats. An overdose of trazodone may result in central nervous system, cardiac, respiratory effects. Signs and symptoms may include dyspnea, bradycardia, hypotension, mental status changes, lack of coordination, and coma, among others. In addition, an overdose may result in priapism, a persistent unrelievable penile tissue erection that may cause permanent damage if not treated promptly. No specific antidote exists for a trazodone overdose. If an overdose occurs, consider the possibility that trazodone may have been combined with other drugs. Contact a poison control center in case of overdose for the most current management guidelines. Dialysis does not accelerate trazodone clearance. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Desyrel, Oleptro •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trazodona Trazodone Trazodonum •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): Trazodone is a serotonin uptake inhibitor used to treat major depressive 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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Tremelimumab interact?

•Drug A: Adalimumab •Drug B: Tremelimumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tremelimumab. •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): Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab. It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. •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): Tremelimumab is a cytotoxic agent that works to decrease tumour growth. It binds to its target, human CTLA-4, with high selectivity and subnanomolar affinity. Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells. In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc 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): T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC). This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells. CD80 and CD86 are also referred to together as B7 molecules. In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions. Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4 and CD8 T cell surface. These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription. B7 molecules act as ligands to both of these receptors, and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells. Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity. •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 solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks. •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 (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively. •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): The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady-state. •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 (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady-state. •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 acute toxicity profile and overdosage of tremelimumab. The maximum tolerated dose in non-human primates was 100 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Imjudo •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): Tremelimumab is an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab.

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 Tremelimumab interact? Information: •Drug A: Adalimumab •Drug B: Tremelimumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Tremelimumab. •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): Tremelimumab is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma in combination with durvalumab. It is also indicated in combination with durvalumab and platinum-based chemotherapy for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. •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): Tremelimumab is a cytotoxic agent that works to decrease tumour growth. It binds to its target, human CTLA-4, with high selectivity and subnanomolar affinity. Tremelimumab caused increased IL-2 production in a dose-dependent manner in ex-vivo blood stimulation assays using peripheral blood mononuclear cells (PBMCs) from healthy volunteers and patients with cancer, indicating that tremelimumab stimulated T cell-mediated cytotoxicity. Tremelimumab also increased the proliferation of effector T cells. In vitro, there was no evidence of nonspecific cytokine release induced by tremelimumab or drug binding to Fc 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): T cell activation is influenced by several processes. T cell receptors (TCR), which are expressed on T cells, bind to the cognate antigen processed and presented by major histocompatibility complex (MHC) expressed on antigen-presenting cells (APC). This interaction generates a TCR signal to activate T cells. In addition to the TCR signal, optimal T cell activation requires a costimulatory signal, produced when CD80 and CD86, expressed on the surface of APCs, bind to receptors expressed on T cells. CD80 and CD86 are also referred to together as B7 molecules. In response to these signals, activated T cells can be further differentiated into specific T cell subtypes with specialized functions. Immune checkpoints are proteins that control the intensity and duration of T cell activation and response. CD28 and CTLA-4 are homologous receptors expressed on CD4 and CD8 T cell surface. These immune checkpoints have opposing regulatory functions on T cell activity: CD28 is a positive regulator of T cell activity, while CTLA-4 is a negative regulator suppressing T cell activation and proliferation, as well as IL-2 gene transcription. B7 molecules act as ligands to both of these receptors, and the balance between CD28 and CTLA-4 expression and signalling influence the extent of T cell activation. In cancer immunotherapy, CTLA-4 has been investigated as a therapeutic target as blocking this receptor can enhance the activation of tumour-specific T cells, allowing them to exert cytotoxic effects on tumour cells. Tremelimumab is an antibody directed against CTLA-4. By binding to CTLA-4, tremelimumab blocks the interaction of CTLA-4 with its ligands, CD80 and CD86, limiting its negative regulatory effect on T cell activation. Inhibition of CTLA-4 leads to increased proliferation of T cells in tumours and promotes T cell-mediated cytotoxicity. •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 solid tumours who received tremelimumab doses 1 mg/kg, 3 mg/kg, and 10 mg/kg (1- to 10-times the approved recommended dosage) once every four weeks for four doses, the AUC of tremelimumab increased proportionally and steady-state was achieved at approximately 12 weeks. •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 (% coefficient of variation [CV%]) of tremelimumab for central (V1) and peripheral (V2) volume of distribution was 3.45 (24%) and 2.66 (34%) L, respectively. •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): The geometric mean (CV%) terminal half-life of tremelimumab was 16.9 days (19%) after a single dose and 18.2 days (19%) during steady-state. •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 (CV%) clearance of tremelimumab was 0.286 L/day (32%) after a single dose and 0.263 L/day (32%) during steady-state. •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 acute toxicity profile and overdosage of tremelimumab. The maximum tolerated dose in non-human primates was 100 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Imjudo •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): Tremelimumab is an anti-CTLA-4 antibody used to treat unresectable hepatocellular carcinoma in combination with durvalumab. 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 Treprostinil interact?

•Drug A: Adalimumab •Drug B: Treprostinil •Severity: MODERATE •Description: The metabolism of Treprostinil 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): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •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 an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream 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): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory 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): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅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): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found 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 terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •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 treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •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): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •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): Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Treprostinil interact? Information: •Drug A: Adalimumab •Drug B: Treprostinil •Severity: MODERATE •Description: The metabolism of Treprostinil 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): The FDA has indicated treprostinil for the treatment of pulmonary arterial hypertension and pulmonary hypertension associated with interstitial lung disease to improve exercise ability. It is also used to treat pulmonary arterial hypertension in patients requiring transition from epoprostenol. The Health Canada label specifies that treprostinil is indicated for the long-term treatment of pulmonary arterial hypertension in NYHA Class III and IV patients who did not respond adequately to conventional therapy. L24244 •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 an analogue of prostacyclin, treprostinil promotes the vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In animals, the vasodilatory effects of treprostinil lead to a reduction of right and left ventricular afterload and an increase in cardiac output and stroke volume. Treprostinil also causes a dose-related negative inotropic and lusitropic effect, and no major effects on cardiac conduction have been detected. Short-lasting effects on QTc were detected in healthy volunteers (n=240) given inhaled single doses of 54 and 84 μg of treprostinil. These effects dissipated rapidly as treprostinil concentrations lowered. When given subcutaneously or intravenously, treprostinil has the potential to reach higher concentrations. The effect of oral treprostinil on QTc has not been evaluated. Due to its ability to inhibit platelet aggregation, treprostinil can increase the risk of bleeding, and patients with low systemic arterial pressure taking treprostinil may experience symptomatic hypotension. The abrupt withdrawal of treprostinil or drastic changes in dose may worsen the symptoms of pulmonary arterial hypertension (PAH). The inhalation of treprostinil can also cause bronchospasms in patients with asthma, chronic obstructive pulmonary disease (COPD), or bronchial hyperreactivity. When given intravenously, treprostinil can lead to infusion complications and increase the risk of bloodstream 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): Treprostinil is a stable analogue of prostacyclin, a prostaglandin that acts as an anti-thrombotic agent and a potent vasodilator. Prostacyclin analogues are useful in the treatment of pulmonary arterial hypertension (PAH), a disease characterized by abnormally high blood pressure in the arteries between the heart and lungs. PAH leads to right heart failure due to the remodelling of pulmonary arteries, and patients with this condition have a poor prognosis. Treprostinil binds and activates the prostacyclin receptor, the prostaglandin D2 receptor 1, and the prostaglandin E2 receptor 2. The activation of these receptors leads to the elevation of intracellular cyclic adenosine monophosphate (cAMP) levels, which consequently promotes the opening of calcium-activated potassium channels that lead to cell hyperpolarization. This mechanism promotes the direct vasodilation of pulmonary and systemic arterial vascular beds and the inhibition of platelet aggregation. In addition to its direct vasodilatory effects, treprostinil inhibits inflammatory 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): After subcutaneous infusion, treprostinil is completely absorbed, with a bioavailability of about 100%, and it reaches steady-state concentrations in approximately 10 hours. The pharmacokinetics of treprostinil follow a two-compartment model and are linear between 2.5 and 125 ng/kg/min. Subcutaneous and intravenous doses of treprostinil are bioequivalent at 10 ng/kg/min. Compared to healthy subjects, patients with mild and moderate hepatic insufficiency had a corresponding C max 2- and 4-times higher and an AUC 0-∞ 3- and 5-times higher when given a subcutaneous treprostinil dose of 10 ng/kg/min for 150 min. When given orally at doses between 0.5 and 15 mg twice a day, treprostinil follows a dose-proportional pharmacokinetic profile. The oral bioavailability of treprostinil is 17%, and drug concentration reaches its highest level between 4 and 6 hours after oral administration. The oral absorption of treprostinil is affected by food. The AUC and C max of oral treprostinil increase 49% and 13%, respectively, when this drug is administered with a high-fat, high-calorie meal. The AUC and C max of inhaled treprostinil were proportional to the doses administered (18 to 90 μg). The bioavailability of inhaled treprostinil was 64% in patients receiving 2 doses of 18 μg, and 72% in patients receiving two doses of 36 μg. Two separate studies that evaluated the pharmacokinetics of inhaled treprostinil at a maintenance dose of 54 μg found that the mean C max was 0.91 and 1.32 ng/mL, respectively, with a corresponding T max of 0.25 and 0.12 hr and a mean AUC of 0.81 and 0.97 hr⋅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): The volume of distribution of treprostinil is 14 L/70 kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): At in vitro concentrations ranging from 330 to 10,000 μg/L, the human plasma protein binding of treprostinil is approximately 91%. This concentration is above what is considered to be clinically relevant. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Treprostinil is mostly metabolized by the liver, mainly by CYP2C8, and by CYP2C9 to a lesser extent. Treprostinil does not have a single major metabolite. The five metabolites detected in urine (HU1 through HU5) accounted for 13.8, 14.3, 15.5, 10.6 and 10.2% of the dose, respectively. One of the metabolites (HU5) is the glucuronide conjugate of treprostinil. HU1, HU2, HU3 and HU4 are formed through the oxidation of the 3-hydroxyloctyl side chain. None of the metabolites of treprostinil appear to be active. In vitro studies suggest that treprostinil does not inhibit or induce any major CYP enzymes. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Treprostinil metabolites are excreted through urine (79%) and feces (13%) over 10 days. Only a small proportion of treprostinil is excreted unchanged. When administered orally, 1.13% and 0.19% of unchanged treprostinil diolamine are found in urine and feces, respectively. When administered subcutaneously, intravenously or by inhalation, 4% of unchanged treprostinil is found 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 terminal elimination half-life of treprostinil is approximately 4 hours, following a two-compartment model. •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 treprostinil is 30 L/hr in a 70 kg person. In patients with mild to moderate hepatic insufficiency, clearance is reduced up to 80%. •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): Treprostinil overdose symptoms are an extension of its dose-limiting pharmacologic effects. These include flushing, headache, hypotension, nausea, vomiting, and diarrhea. Most overdose events were self-limiting and resolved by reducing or withholding treprostinil. In studies where treprostinil was infused using an external pump, several patients received an overdose due to an accidental bolus administration, errors in the programmed delivery rate and incorrect prescriptions. Only two cases of of substantial hemodynamic concern were detected among patients that received an excess of treprostinil. A pediatric patient that accidentally received 7.5 mg of treprostinil via a central venous catheter presented flushing, headache, nausea, vomiting, hypotension, and seizure-like activity with loss of consciousness for several minutes. A rat study that evaluated the carcinogenic effects of inhaled treprostinil, found no evidence of carcinogenicity in levels up to 35 times the clinical exposure obtained with a maintenance dose of 54 μg. The infusion of treprostinil sodium did not affect fertility or mating performance in rats given subcutaneous treprostinil. Treprostinil did not show mutagenic or clastogenic effects in in vitro or in vivo studies. There was no significant increase of tumors in rats given up to 10 mg/kg/day of oral treprostinil diolamine. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Orenitram, Remodulin, Tyvaso •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): Treprostinil is a prostacyclin vasodilator for the treatment of pulmonary arterial hypertension to relieve exercise associated symptoms and to prevent clinical deterioration after stopping epoprostenol. 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 Tretinoin interact?

•Drug A: Adalimumab •Drug B: Tretinoin •Severity: MODERATE •Description: The metabolism of Tretinoin 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): Oral tretinoin is indicated for induction of remission in adults and pediatric patients one year of age and older with acute promyelocytic leukemia (APL), characterized by the presence of t(15;17) translocation or presence of PML/RARα gene expression and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. Topical tretinoin is also indicated alone or in combination with benzoyl peroxide or clindamycin for the treatment of acne vulgaris. It is also used in prescription and over-the-counter for treating various skin conditions such as melasma, hyperpigmentation, and photoaging alone or 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): Tretinoin is a vitamin A derivative that promotes cell production, proliferation, and differentiation. When used topically, tretinoin regulates epidermal cell turnover and collagen production. It also prevents collagen loss, reduces inflammation, and blocks the induction of matrix metalloproteinase (MMP), which are enzymes that disrupt collagen and elastic fibres. In short-term and long-term studies, topical application of tretinoin at doses ranging from 0.001% to 0.1% was associated with improvements in clinical signs of photoaging and fine wrinkles, increased epidermal thickness, compaction of the stratum corneum, and decreased melanin content. It also improved melanocyte differentiation and distribution, promotion of epidermal hyperplasia, and angiogenesis. Tretinoin exhibits antineoplastic activities when given orally. Tretinoin was shown to induce differentiation in tumour cells. It induced cytodifferentiation and decreased acute promyelocytic leukemia (APL) cell proliferation in culture and in vivo. In patients with APL, tretinoin promoted the initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission. •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 tretinoin in skin conditions and acute promyelocytic leukemia (APL) has not been fully elucidated; however, several proposed mechanisms exist. Tretinoin is believed to exert its pharmacological actions by binding to and activating two types of nuclear receptors - retinoic acid receptors (RARs) alpha, beta, and gamma and retinoid X receptors (RXRs). In the human skin, RARs (especially RAR-alpha) form heterodimers with RXR to act as inducible transcription regulators of genes involved in cell differentiation by binding to retinoic acid response elements. Tretinoin binds to RXRs to promote epidermal proliferation. It also blocks the actions of inflammatory mediators, enhancing procollagen production and collagen type I and III formations. Some animal and human studies suggest that tretinoin induces the expression of transforming growth factor beta (TGF-β), which stimulates the transcription of several types of collagen messenger RNA. Collagen formation curtails further solar UV-induced skin damage and aging processes. Acne is associated with abnormal follicular formation from excessive keratinization of epithelial cells. Tretinoin promotes cornified cell detachment and enhances keratinocyte shedding. It also stimulates mitotic activity and loosely-adherent corneocyte turnover to expel comedo contents, reducing microcomedo precursor lesions of acne vulgaris. Tretinoin may reduce epidermal melanin and pigmentation by increasing keratinocyte turnover and reducing tyrosinase activity. RAR-alpha and -beta have also been implicated in APL. APL is characterized by a t(15;17) chromosomal translocation, which fuses the promyelocytic myeloid leukemia (PML) gene with the RAR-alpha gene. The resulting PML-RAR-alpha fusion protein plays a role in the pathogenesis of APL by aberrating promyelocyte differentiation. The PML-RAR-alpha fusion protein is found to be predominant in leukemic cells, exerting a dominant negative effect on RAR, RXR and PML function. Tretinoin induces terminal differentiation in hemopoietic precursor cell lines and APL cells. Tretinoin is believed to promote caspase-mediated cleavage and proteasome-dependent degradation to cause apoptosis and degradation of the PML-RAR-alpha fusion protein. It may also convert the fusion protein from a transcription repressor to an activator. •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): Tretinoin applied topically is expected to remain on the stratum corneum and undergo minimal systemic absorption. In one study, the topical application of radiolabelled tretinoin for 28 days was associated with a total percutaneous absorption of 2%. The extent of absorption was examined after a once-daily application of 1.9 g of the combination product with benzoyl peroxide for 14 days. On Day 14, at steady-state, the mean C max was 0.15-0.19 ng/mL for tretinoin, 0.27-0.34 ng/mL for the metabolite 4-keto 13-cis retinoic acid, and 0.13-0.28 ng/mL for 13-cis retinoic acid, respectively. The C max varied across different age groups (children, adolescents, and adults). The corresponding ranges for the mean AUC 0-24 were 0.63-2.06, 2.39-2.89, and 0.96-1.99 ng*h/mL. Following oral administration, the absolute bioavailability of tretinoin was approximately 50%. While the effect of food on tretinoin is unclear, food increases the oral absorption of retinoids, as a class. When the oral dose of 22.5 mg/m tretinoin was administered twice daily, the mean ± SD C max was 394 ± 89 ng/mL after the first dose and 138 ± 139 ng/mL after one week of continuous treatment. The area under the curve (AUC) was 537 ± 191 ng·h/mL after the first dose and 249 ± 185 ng·h/mL after one week of continuous treatment. The T max was between one and two 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): Tretinoin is rapidly and extensively distributed to tissues following oral administration but does not cross the blood-brain barrier. The apparent volume of distribution (V d ) of intravenous tretinoin is dose-dependent and significantly greater at low doses. The V d was 0.52 ± 0.12 L/kg after 0.0125 mg/kg and 0.21 ± 0.05 L/kg after 0.25 mg/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of tretinoin is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the 10 to 500 ng/mL concentration range. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tretinoin is rapidly metabolized to form various oxidized and conjugated metabolites. It forms several metabolites stereoisomerization derivatives (9- cis -retinoic acid or alitretinoin and 13- cis -retinoic acid or isotretinoin ), oxidation derivatives (4-hydroxy-retinoic acid, 4-oxo-retinoic acid, 18-hydroxy-retinoic acid, 5,6-epoxy-retinoic acid, 3,4-didehydro-retinoic acid and retinotaurine), stereoisomerization and oxidation derivatives (13- cis -4-oxo-retinoic acid), glucuronidation derivatives (retinoyl beta-glucuronide, 13- cis -retinoyl beta-glucuronide, 4-oxo-retinoyl beta-glucuronide, 5,6-epoxyretinoyl beta-glucuronide and 13- cis -4-oxo-retinoyl beta-glucuronide), nonpolar metabolites of retinoic acid, and retinoic acid esters. Tretinoin is metabolized by several CYP enzymes, including CYP3A4, CYP2C8, and CYP2E. It also undergoes glucuronidation by UGT2B7. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. When the plasma concentrations decreased to one-third of their day-one concentrations after one week of continuous therapy, tretinoin induced its own metabolism. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tretinoin metabolites are excreted in bile and urine. Following administration of radiolabeled tretinoin at doses of 2.75 mg and 50 mg - which are 0.53 to 9.6 times the approved recommended dosage based on 1.7 m, respectively - approximately 63% of the radioactivity was recovered in the urine within 72 hours, and 31% appeared in the feces within six 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 elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. •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. •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 2000 mg/kg. The dermal LD 50 in rabbits is >2500 mg/kg. Reversible signs of hypervitaminosis A, such as headache, nausea, vomiting, and mucocutaneous symptoms, are expected to appear in tretinoin overdose. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia: these symptoms have quickly resolved without apparent residual effects. here is no specific treatment in the case of an overdose and it is advised to treat patients experiencing tretinoin overdose in a special hematological unit. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Altreno, Atralin, Biacna, Refissa, Renova, Retin-A, Stieva-A, Tri-luma, Twyneo, Veltin, Vesanoid, Ziana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide retinoique all trans Retinoic acid all trans-Retinoic acid all-(E)-Retinoic acid all-trans-Retinoic acid all-trans-Tretinoin all-trans-Vitamin A acid all-trans-Vitamin A1 acid ATRA beta-Retinoic acid Retinoic acid Retionic acid trans-Retinoic acid Tretin M Tretinoin Tretinoina Trétinoïne Tretinoinum Vitamin A acid •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): Tretinoin is a vitamin A derivative used to treat acne vulgaris and certain types of promyelocytic leukemia, as well as various skin conditions in over-the-counter medications.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Tretinoin interact? Information: •Drug A: Adalimumab •Drug B: Tretinoin •Severity: MODERATE •Description: The metabolism of Tretinoin 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): Oral tretinoin is indicated for induction of remission in adults and pediatric patients one year of age and older with acute promyelocytic leukemia (APL), characterized by the presence of t(15;17) translocation or presence of PML/RARα gene expression and who are refractory to or who have relapsed from anthracycline chemotherapy or for whom anthracycline-based chemotherapy is contraindicated. Topical tretinoin is also indicated alone or in combination with benzoyl peroxide or clindamycin for the treatment of acne vulgaris. It is also used in prescription and over-the-counter for treating various skin conditions such as melasma, hyperpigmentation, and photoaging alone or 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): Tretinoin is a vitamin A derivative that promotes cell production, proliferation, and differentiation. When used topically, tretinoin regulates epidermal cell turnover and collagen production. It also prevents collagen loss, reduces inflammation, and blocks the induction of matrix metalloproteinase (MMP), which are enzymes that disrupt collagen and elastic fibres. In short-term and long-term studies, topical application of tretinoin at doses ranging from 0.001% to 0.1% was associated with improvements in clinical signs of photoaging and fine wrinkles, increased epidermal thickness, compaction of the stratum corneum, and decreased melanin content. It also improved melanocyte differentiation and distribution, promotion of epidermal hyperplasia, and angiogenesis. Tretinoin exhibits antineoplastic activities when given orally. Tretinoin was shown to induce differentiation in tumour cells. It induced cytodifferentiation and decreased acute promyelocytic leukemia (APL) cell proliferation in culture and in vivo. In patients with APL, tretinoin promoted the initial maturation of the primitive promyelocytes derived from the leukemic clone, followed by a repopulation of the bone marrow and peripheral blood by normal, polyclonal hematopoietic cells in patients achieving complete remission. •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 tretinoin in skin conditions and acute promyelocytic leukemia (APL) has not been fully elucidated; however, several proposed mechanisms exist. Tretinoin is believed to exert its pharmacological actions by binding to and activating two types of nuclear receptors - retinoic acid receptors (RARs) alpha, beta, and gamma and retinoid X receptors (RXRs). In the human skin, RARs (especially RAR-alpha) form heterodimers with RXR to act as inducible transcription regulators of genes involved in cell differentiation by binding to retinoic acid response elements. Tretinoin binds to RXRs to promote epidermal proliferation. It also blocks the actions of inflammatory mediators, enhancing procollagen production and collagen type I and III formations. Some animal and human studies suggest that tretinoin induces the expression of transforming growth factor beta (TGF-β), which stimulates the transcription of several types of collagen messenger RNA. Collagen formation curtails further solar UV-induced skin damage and aging processes. Acne is associated with abnormal follicular formation from excessive keratinization of epithelial cells. Tretinoin promotes cornified cell detachment and enhances keratinocyte shedding. It also stimulates mitotic activity and loosely-adherent corneocyte turnover to expel comedo contents, reducing microcomedo precursor lesions of acne vulgaris. Tretinoin may reduce epidermal melanin and pigmentation by increasing keratinocyte turnover and reducing tyrosinase activity. RAR-alpha and -beta have also been implicated in APL. APL is characterized by a t(15;17) chromosomal translocation, which fuses the promyelocytic myeloid leukemia (PML) gene with the RAR-alpha gene. The resulting PML-RAR-alpha fusion protein plays a role in the pathogenesis of APL by aberrating promyelocyte differentiation. The PML-RAR-alpha fusion protein is found to be predominant in leukemic cells, exerting a dominant negative effect on RAR, RXR and PML function. Tretinoin induces terminal differentiation in hemopoietic precursor cell lines and APL cells. Tretinoin is believed to promote caspase-mediated cleavage and proteasome-dependent degradation to cause apoptosis and degradation of the PML-RAR-alpha fusion protein. It may also convert the fusion protein from a transcription repressor to an activator. •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): Tretinoin applied topically is expected to remain on the stratum corneum and undergo minimal systemic absorption. In one study, the topical application of radiolabelled tretinoin for 28 days was associated with a total percutaneous absorption of 2%. The extent of absorption was examined after a once-daily application of 1.9 g of the combination product with benzoyl peroxide for 14 days. On Day 14, at steady-state, the mean C max was 0.15-0.19 ng/mL for tretinoin, 0.27-0.34 ng/mL for the metabolite 4-keto 13-cis retinoic acid, and 0.13-0.28 ng/mL for 13-cis retinoic acid, respectively. The C max varied across different age groups (children, adolescents, and adults). The corresponding ranges for the mean AUC 0-24 were 0.63-2.06, 2.39-2.89, and 0.96-1.99 ng*h/mL. Following oral administration, the absolute bioavailability of tretinoin was approximately 50%. While the effect of food on tretinoin is unclear, food increases the oral absorption of retinoids, as a class. When the oral dose of 22.5 mg/m tretinoin was administered twice daily, the mean ± SD C max was 394 ± 89 ng/mL after the first dose and 138 ± 139 ng/mL after one week of continuous treatment. The area under the curve (AUC) was 537 ± 191 ng·h/mL after the first dose and 249 ± 185 ng·h/mL after one week of continuous treatment. The T max was between one and two 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): Tretinoin is rapidly and extensively distributed to tissues following oral administration but does not cross the blood-brain barrier. The apparent volume of distribution (V d ) of intravenous tretinoin is dose-dependent and significantly greater at low doses. The V d was 0.52 ± 0.12 L/kg after 0.0125 mg/kg and 0.21 ± 0.05 L/kg after 0.25 mg/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of tretinoin is greater than 95%, predominately to albumin. Plasma protein binding remains constant over the 10 to 500 ng/mL concentration range. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tretinoin is rapidly metabolized to form various oxidized and conjugated metabolites. It forms several metabolites stereoisomerization derivatives (9- cis -retinoic acid or alitretinoin and 13- cis -retinoic acid or isotretinoin ), oxidation derivatives (4-hydroxy-retinoic acid, 4-oxo-retinoic acid, 18-hydroxy-retinoic acid, 5,6-epoxy-retinoic acid, 3,4-didehydro-retinoic acid and retinotaurine), stereoisomerization and oxidation derivatives (13- cis -4-oxo-retinoic acid), glucuronidation derivatives (retinoyl beta-glucuronide, 13- cis -retinoyl beta-glucuronide, 4-oxo-retinoyl beta-glucuronide, 5,6-epoxyretinoyl beta-glucuronide and 13- cis -4-oxo-retinoyl beta-glucuronide), nonpolar metabolites of retinoic acid, and retinoic acid esters. Tretinoin is metabolized by several CYP enzymes, including CYP3A4, CYP2C8, and CYP2E. It also undergoes glucuronidation by UGT2B7. The metabolites 4-oxo retinoic acid and 4-oxo trans retinoic acid glucuronide have one-third of the pharmacological activity of the parent compound. When the plasma concentrations decreased to one-third of their day-one concentrations after one week of continuous therapy, tretinoin induced its own metabolism. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Tretinoin metabolites are excreted in bile and urine. Following administration of radiolabeled tretinoin at doses of 2.75 mg and 50 mg - which are 0.53 to 9.6 times the approved recommended dosage based on 1.7 m, respectively - approximately 63% of the radioactivity was recovered in the urine within 72 hours, and 31% appeared in the feces within six 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 elimination half-life of tretinoin following initial dosing is 0.5 to 2 hours in patients with APL. •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. •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 2000 mg/kg. The dermal LD 50 in rabbits is >2500 mg/kg. Reversible signs of hypervitaminosis A, such as headache, nausea, vomiting, and mucocutaneous symptoms, are expected to appear in tretinoin overdose. Overdosage with other retinoids has been associated with transient headache, facial flushing, cheilosis, abdominal pain, dizziness and ataxia: these symptoms have quickly resolved without apparent residual effects. here is no specific treatment in the case of an overdose and it is advised to treat patients experiencing tretinoin overdose in a special hematological unit. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Altreno, Atralin, Biacna, Refissa, Renova, Retin-A, Stieva-A, Tri-luma, Twyneo, Veltin, Vesanoid, Ziana •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Acide retinoique all trans Retinoic acid all trans-Retinoic acid all-(E)-Retinoic acid all-trans-Retinoic acid all-trans-Tretinoin all-trans-Vitamin A acid all-trans-Vitamin A1 acid ATRA beta-Retinoic acid Retinoic acid Retionic acid trans-Retinoic acid Tretin M Tretinoin Tretinoina Trétinoïne Tretinoinum Vitamin A acid •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): Tretinoin is a vitamin A derivative used to treat acne vulgaris and certain types of promyelocytic leukemia, as well as various skin conditions in over-the-counter medications. 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 Triamcinolone interact?

•Drug A: Adalimumab •Drug B: Triamcinolone •Severity: MODERATE •Description: The metabolism of Triamcinolone 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): Triamcinolone hexacetonide injections are indicated for intralesional administration in alopecia areata, discoid lupus erythematosus, keloids, and necrobiosis lipoidica diabeticorum. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. Triamcinolone acetonide spray and cream are indicated for the treatment of inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. A triamcinolone acetonide 10mg/mL or 40mg/mL injection is indicated intra-articularly for acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis. The same 10mg/mL injection is indicated by the intralesional route for the treatment of alopecia areata, discoid lupus erythematosus, keloids, necrobiosis lipoidica diabeticorum, and tumors of an aponeurosis or tendon. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. The 40mg/mL injection is indicated intramuscularly for controlling severe allergic conditions such as asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity, perennial or seasonal allergic rhinitis, serum sickness, and transfusion reactions; treatment of bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, Stevens-Johnson syndrome, congenital adrenal hyperplasia, hypercalcemia in cancer, nonsuppurative thyroiditis, autoimmune hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, secondary thrombocytopenia, trichinosis, tuberculous meningitis, acute exacerbations of multiple sclerosis or cerebral edema, sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammation, berylliosis, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis, dermatomyositis, polymyositis, and systemic lupus erythematosus; adjunct treatment of adrenocortical insufficiency, regional enteritis, ulcerative colitis, fulminating or disseminated pulmonary tuberculosis, acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis; palliative management of leukemia and lymphoma; induction of diuresis or remission of proteinuria in idiopathic nephrotic syndrome or lupus erythematosus. A triamcinolone intravitreal injection is indicated for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions. The intravitreal injection is also used for visualization during vitrectomy. An extended release suspension is indicated intra-articularly for management of pain in osteoarthritis of the knee. A triamcinolone acetonide suspension for injection into the suprachoroidal space is indicated for the treatment of macular edema associated with uveitis. •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): Triamcinolone is a corticosteroid with anti-inflammatory properties. These properties are used to treat inflammation in conditions that affect various organs and tissues. Triamcinolone should not be administered as an epidural injection. •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): Corticosteroids like triamcinolone inhibit phospholipase A2 on cell membranes, preventing the breakdown of lysosomal membranes of leukocytes, which in turn prevent the formation of arachidonic acid, which decrease expression of cyclooxygenase and lipoxygenase, inhibiting synthesis of prostaglandins and leukotrienes. Anti-inflammatory activity occurs via reversal of vascular dilation and reducing permeability, which prevents macrophage and leukocyte migration. Triamcinolone also inhibits nuclear factor kappa-B, which decreases the production of pro-inflammatory signals such as interleukin-6, interleukin-8, and monocyte chemoattractant protein-1. •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 16mg oral dose of triamcinolone reaches a C max of 5.23±0.84ng/mL with a T max of 2.24±0.78h and an AUC of 36.0±6.2ng*h/mL. A 2mg intravenous dose of triamcinolone acetonide has an AUC of 57.7ng*h/mL. The bioavailability of 800µg of inhaled triamcinolone acetonide is 25%, with 10.4% coming from pulmonary absorption and the rest being accounted for by deposition on the oral mucosa and other underlying factors. An inhaled dose of triamcinolone acetonide reaches a C max of 0.92ng/mL with a T max of 1.74h and an AUC of 5.12ng*h/mL. The fraction of an inhaled dose that is actually absorbed via the pulmonary route reaches a C max of 0.55ng/mL with a T max of 0.66h and an AUC of 2.15ng*h/mL. A 16mg oral dose of triamcinolone diacetate reaches a C max of 5.33±1.55ng/mL with a T max of 1.86±0.47h and an AUC of 32.7±9.9ng*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 apparent volume of distribution of triamcinolone is 115.2±10L. The mean apparent volume of distribution of triamcinolone acetonide is 1.96L/kg. The apparent volume of distribution of triamcinolone diacetate is 119.7±33.14L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Triamcinolone is mostly bound to corticosteroid-binding globulin or serum albumin. Triamcinolone acetonide is approximately 68% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The major metabolite of triamcinolone is 6-beta-hydroxy-triamcinolone. Data regarding the metabolism of triamcinolone is not readily available. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 20% of a dose of triamcinolone is recovered in the urine as the unchanged drug, 25% is recovered as 6-beta-hydroxy-triamcinolone, and 5% is recovered as unidentified 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 half life of triamcinolone is 2.7h. The mean terminal elimination half life following an inhaled dose of triamcinolone acetonide is 2.4h. The half life of triamcinolone diacetate is 2.8h. •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): The clearance of triamcinolone is 28.6±5.6L/h. The mean total body clearance of triamcinolone acetonide is 0.57L/h. The clearance of triamcinolone diacetate is 34.4±10.6L/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 subcutaneous LD 50 of triamcinolone acetonide in rats is 13,100µg/kg and in mice is 132mg/kg. The oral LD 50 in rats is 1451mg/kg and in mice is 2168mg/kg.[LD 50 ] The intraperitoneal LD 50 in mice is 105mg/kg.[LD 50 ] Patients experiencing an overdose may develop Cushing's syndrome. This overdose may be treated with supportive therapy and mifepristone for its antiglucocorticoid activity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Allernaze, Aristocort, Aristocort R, Juulissa Pharmapak, Kenalog, Kourzeq, Marcaine, Nasacort, Oracort, Oralone, Pediaderm Ta, Triaderm, Trianex, Triderm, Triesence, Triloan Suik, Tritocin, Viaderm Kc, Xipere, Zilretta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxyprednisolone Tiamcinolonum Triamcinolona Triamcinolone Triamcinolonum •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): Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Triamcinolone interact? Information: •Drug A: Adalimumab •Drug B: Triamcinolone •Severity: MODERATE •Description: The metabolism of Triamcinolone 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): Triamcinolone hexacetonide injections are indicated for intralesional administration in alopecia areata, discoid lupus erythematosus, keloids, and necrobiosis lipoidica diabeticorum. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. Triamcinolone acetonide spray and cream are indicated for the treatment of inflammatory and pruritic manifestations of corticosteroid responsive dermatoses. A triamcinolone acetonide 10mg/mL or 40mg/mL injection is indicated intra-articularly for acute gouty arthritis, acute and subacute bursitis, acute nonspecific tenosynovitis, epicondylitis, rheumatoid arthritis, and synovitis of osteoarthritis. The same 10mg/mL injection is indicated by the intralesional route for the treatment of alopecia areata, discoid lupus erythematosus, keloids, necrobiosis lipoidica diabeticorum, and tumors of an aponeurosis or tendon. This formulation can also be used for localized hypertrophic infiltrated inflammatory lesions of granuloma annulare, lichen planus, lichen simplex chronicus, and psoriatic plaques. The 40mg/mL injection is indicated intramuscularly for controlling severe allergic conditions such as asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity, perennial or seasonal allergic rhinitis, serum sickness, and transfusion reactions; treatment of bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, Stevens-Johnson syndrome, congenital adrenal hyperplasia, hypercalcemia in cancer, nonsuppurative thyroiditis, autoimmune hemolytic anemia, Diamond-Blackfan anemia, pure red cell aplasia, secondary thrombocytopenia, trichinosis, tuberculous meningitis, acute exacerbations of multiple sclerosis or cerebral edema, sympathetic ophthalmia, temporal arteritis, uveitis, ocular inflammation, berylliosis, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis, dermatomyositis, polymyositis, and systemic lupus erythematosus; adjunct treatment of adrenocortical insufficiency, regional enteritis, ulcerative colitis, fulminating or disseminated pulmonary tuberculosis, acute gouty arthritis, acute rheumatic carditis, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis; palliative management of leukemia and lymphoma; induction of diuresis or remission of proteinuria in idiopathic nephrotic syndrome or lupus erythematosus. A triamcinolone intravitreal injection is indicated for the treatment of sympathetic ophthalmia, temporal arteritis, uveitis, and ocular inflammatory conditions. The intravitreal injection is also used for visualization during vitrectomy. An extended release suspension is indicated intra-articularly for management of pain in osteoarthritis of the knee. A triamcinolone acetonide suspension for injection into the suprachoroidal space is indicated for the treatment of macular edema associated with uveitis. •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): Triamcinolone is a corticosteroid with anti-inflammatory properties. These properties are used to treat inflammation in conditions that affect various organs and tissues. Triamcinolone should not be administered as an epidural injection. •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): Corticosteroids like triamcinolone inhibit phospholipase A2 on cell membranes, preventing the breakdown of lysosomal membranes of leukocytes, which in turn prevent the formation of arachidonic acid, which decrease expression of cyclooxygenase and lipoxygenase, inhibiting synthesis of prostaglandins and leukotrienes. Anti-inflammatory activity occurs via reversal of vascular dilation and reducing permeability, which prevents macrophage and leukocyte migration. Triamcinolone also inhibits nuclear factor kappa-B, which decreases the production of pro-inflammatory signals such as interleukin-6, interleukin-8, and monocyte chemoattractant protein-1. •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 16mg oral dose of triamcinolone reaches a C max of 5.23±0.84ng/mL with a T max of 2.24±0.78h and an AUC of 36.0±6.2ng*h/mL. A 2mg intravenous dose of triamcinolone acetonide has an AUC of 57.7ng*h/mL. The bioavailability of 800µg of inhaled triamcinolone acetonide is 25%, with 10.4% coming from pulmonary absorption and the rest being accounted for by deposition on the oral mucosa and other underlying factors. An inhaled dose of triamcinolone acetonide reaches a C max of 0.92ng/mL with a T max of 1.74h and an AUC of 5.12ng*h/mL. The fraction of an inhaled dose that is actually absorbed via the pulmonary route reaches a C max of 0.55ng/mL with a T max of 0.66h and an AUC of 2.15ng*h/mL. A 16mg oral dose of triamcinolone diacetate reaches a C max of 5.33±1.55ng/mL with a T max of 1.86±0.47h and an AUC of 32.7±9.9ng*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 apparent volume of distribution of triamcinolone is 115.2±10L. The mean apparent volume of distribution of triamcinolone acetonide is 1.96L/kg. The apparent volume of distribution of triamcinolone diacetate is 119.7±33.14L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Triamcinolone is mostly bound to corticosteroid-binding globulin or serum albumin. Triamcinolone acetonide is approximately 68% protein bound in plasma. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The major metabolite of triamcinolone is 6-beta-hydroxy-triamcinolone. Data regarding the metabolism of triamcinolone is not readily available. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 20% of a dose of triamcinolone is recovered in the urine as the unchanged drug, 25% is recovered as 6-beta-hydroxy-triamcinolone, and 5% is recovered as unidentified 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 half life of triamcinolone is 2.7h. The mean terminal elimination half life following an inhaled dose of triamcinolone acetonide is 2.4h. The half life of triamcinolone diacetate is 2.8h. •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): The clearance of triamcinolone is 28.6±5.6L/h. The mean total body clearance of triamcinolone acetonide is 0.57L/h. The clearance of triamcinolone diacetate is 34.4±10.6L/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 subcutaneous LD 50 of triamcinolone acetonide in rats is 13,100µg/kg and in mice is 132mg/kg. The oral LD 50 in rats is 1451mg/kg and in mice is 2168mg/kg.[LD 50 ] The intraperitoneal LD 50 in mice is 105mg/kg.[LD 50 ] Patients experiencing an overdose may develop Cushing's syndrome. This overdose may be treated with supportive therapy and mifepristone for its antiglucocorticoid activity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Allernaze, Aristocort, Aristocort R, Juulissa Pharmapak, Kenalog, Kourzeq, Marcaine, Nasacort, Oracort, Oralone, Pediaderm Ta, Triaderm, Trianex, Triderm, Triesence, Triloan Suik, Tritocin, Viaderm Kc, Xipere, Zilretta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Fluoxyprednisolone Tiamcinolonum Triamcinolona Triamcinolone Triamcinolonum •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): Triamcinolone is a glucocorticoid used to treat a wide variety of inflammatory conditions of organ systems and tissues. 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 Triamterene interact?

•Drug A: Adalimumab •Drug B: Triamterene •Severity: MODERATE •Description: The metabolism of Triamterene 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): Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism. Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides. •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): Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide. •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): Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule, which are transmembrane channels that normally promote sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the luminal membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases sodium excretion, thereby increasing the excretion of water, and reducing the excess loss of potassium, hydrogen, and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost completely abolishing Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium. •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): Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents. •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 pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 67% bound to proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene 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): The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug. •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 plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers. •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 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage. In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dyrenium, Maxzide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teridin Triamteren Triamterena Triamtérène Triamterene Triamtereno Triamterenum •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): Triamterene is a potassium-sparing diuretic used in the treatment of edema and in the management of hypertension.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Triamterene interact? Information: •Drug A: Adalimumab •Drug B: Triamterene •Severity: MODERATE •Description: The metabolism of Triamterene 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): Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism. Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides. •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): Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide. •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): Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule, which are transmembrane channels that normally promote sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the luminal membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases sodium excretion, thereby increasing the excretion of water, and reducing the excess loss of potassium, hydrogen, and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost completely abolishing Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium. •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): Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents. •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 pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 67% bound to proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene 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): The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug. •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 plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers. •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 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage. In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dyrenium, Maxzide •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Teridin Triamteren Triamterena Triamtérène Triamterene Triamtereno Triamterenum •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): Triamterene is a potassium-sparing diuretic used in the treatment of edema and in the management of hypertension. 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 Triazolam interact?

•Drug A: Adalimumab •Drug B: Triazolam •Severity: MODERATE •Description: The metabolism of Triazolam 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): For the short-term treatment of insomnia. •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): A short-acting benzodiazepine used as a hypnotic agent in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. Triazolam has a shorter half-life than chlordiazepoxide, flurazepam, and prazepam and does not generate active metabolites. •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): Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA A ) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. •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 44% (oral) and 53% (sublingual). •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. Small amounts of unmetabolized triazolam appear in the urine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of 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): 1.5-5.5 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): Symptoms of overdose include drowsiness, slurred speech, motor inco-ordination, coma, and respiratory depression. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Halcion •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): Triazolam is a benzodiazepine used for short term treatment of 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 CYP3A5 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Triazolam interact? Information: •Drug A: Adalimumab •Drug B: Triazolam •Severity: MODERATE •Description: The metabolism of Triazolam 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): For the short-term treatment of insomnia. •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): A short-acting benzodiazepine used as a hypnotic agent in the treatment of insomnia. Some countries temporarily withdrew triazolam from the market because of concerns about adverse reactions, mostly psychological, associated with higher dose ranges. Its use at lower doses with appropriate care and labeling has been reaffirmed by the FDA and most other countries. Triazolam has a shorter half-life than chlordiazepoxide, flurazepam, and prazepam and does not generate active metabolites. •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): Benzodiazepines bind nonspecifically to bezodiazepine receptors BNZ1, which mediates sleep, and BNZ2, which affects affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA A ) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell. •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 44% (oral) and 53% (sublingual). •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. Small amounts of unmetabolized triazolam appear in the urine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Triazolam and its metabolites, principally as conjugated glucuronides, which are presumably inactive, are excreted primarily in the urine. Only small amounts of unmetabolized triazolam appear in the urine. The two primary metabolites accounted for 79.9% of 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): 1.5-5.5 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): Symptoms of overdose include drowsiness, slurred speech, motor inco-ordination, coma, and respiratory depression. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Halcion •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): Triazolam is a benzodiazepine used for short term treatment of 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 CYP3A5 substrates. The severity of the interaction is moderate.

Does Adalimumab and Triclabendazole interact?

•Drug A: Adalimumab •Drug B: Triclabendazole •Severity: MODERATE •Description: The metabolism of Triclabendazole 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): This drug is indicated for the treatment of fascioliasis in patients aged 6 years old 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): Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths. Effect on QT interval This drug may prolong the cardiac QT interval. Monitor ECG in patients with a history of QT prolongation or who are taking medications known to prolong the QT 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): Triclabendazole is an anthelmintic agent against Fasciola species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites ( sulfoxide and sulfone ) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. A note on resistance In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. •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 a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. Effect of Food Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed 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 apparent volume of distribution (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, in vitro. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found 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 plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 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): 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): >8 gm/kg; Oral LD50 (mouse): >8 gm/kg A note on the use in pregnancy There are no available data on triclabendazole use in pregnant women to calculate a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not demonstrated an increased risk of increased fetal abnormalities with exposure to triclabendazole during the organogenesis period at doses which were about 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg. Carcinogenesis/Mutagenesis No genotoxic risk was noted for triclabendazole tested in 6 genotoxicity in vitro and in vivo assays. Impairment of Fertility No drug-related effects on reproductive performance, mating ratios or indices of fertility have been observed in a 2-generation reproductive and developmental toxicity study in rats. A note on use in breastfeeding There are no human findings on the presence of triclabendazole in milk, the effects on a nursing infant, or the effects on maternal milk production. The results of animal studies indicate that triclabendazole is found in goat milk when given as a single dose to a lactating female goat. When a drug is found to be present in animal milk, the likelihood that it will be found in human milk is high. Excercise caution if this drug is administered during nursing. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Egaten •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): Triclabendazole is an anthelmintic drug used to treat fascioliasis.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Triclabendazole interact? Information: •Drug A: Adalimumab •Drug B: Triclabendazole •Severity: MODERATE •Description: The metabolism of Triclabendazole 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): This drug is indicated for the treatment of fascioliasis in patients aged 6 years old 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): Triclabendazole and its metabolites are active against both the immature and mature worms of Fasciola hepatica and Fasciola gigantica helminths. Effect on QT interval This drug may prolong the cardiac QT interval. Monitor ECG in patients with a history of QT prolongation or who are taking medications known to prolong the QT 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): Triclabendazole is an anthelmintic agent against Fasciola species. The mechanism of action against Fasciola species is not fully understood at this time. In vitro studies and animal studies suggest that triclabendazole and its active metabolites ( sulfoxide and sulfone ) are absorbed by the outer body covering of the immature and mature worms, causing a reduction in the resting membrane potential, the inhibition of tubulin function as well as protein and enzyme synthesis necessary for survival. These metabolic disturbances lead to an inhibition of motility, disruption of the worm outer surface, in addition to the inhibition of spermatogenesis and egg/embryonic cells. A note on resistance In vitro studies, in vivo studies, as well as case reports suggest a possibility for the development of resistance to triclabendazole. The mechanism of resistance may be multifactorial and include changes in drug uptake/efflux mechanisms, target molecules, and changes in drug metabolism. The clinical significance of triclabendazole resistance in humans is not yet elucidated. •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 a single oral dose of 10 mg/kg triclabendazole with a 560-kcal meal to patients diagnosed with fascioliasis, mean peak plasma concentrations (Cmax) for triclabendazole, the sulfoxide, and sulfone metabolites were 1.16, 38.6, and 2.29 μmol/L, respectively. The area under the curve (AUC) for triclabendazole, the sulfoxide and sulfone metabolites were 5.72, 386, and 30.5 μmol∙h/L, respectively. After the oral administration of a single dose of triclabendazole at 10 mg/kg with a 560 calorie meal to patients with fascioliasis, the median Tmax for the parent compound as well as the active sulfoxide metabolite was 3 to 4 hours. Effect of Food Cmax and AUC of triclabendazole and sulfoxide metabolite increased about 2-3 times when triclabendazole was administered as a single dose at 10 mg/kg with a meal containing approximately 560 calories. Additionally, the sulfoxide metabolite Tmax increased from 2 hours in fasting subjects to 4 hours in fed 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 apparent volume of distribution (Vd) of the sulfoxide metabolite in fed patients is about 1 L/kg. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein-binding of triclabendazole, sulfoxide metabolite and sulfone metabolite in human plasma was 96.7%, 98.4% and 98.8% respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Based on in vitro studies, triclabendazole is mainly metabolized by CYP1A2 enzyme (approximately 64%) into its active sulfoxide metabolite and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, CYP3A, and FMO (flavin containing monooxygenase). This sulfoxide metabolite is further metabolized mainly by CYP2C9 to the active sulfone metabolite, and to a smaller extent by CYP1A1, CYP1A2, CYP1B1, CYP2C19, CYP2D6, and CYP3A4, in vitro. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): No data regarding excretion is available in humans. In animals, triclabendazole is primarily excreted by the biliary tract in the feces (90%), together with the sulfoxide and sulfone metabolite. Less than 10% of an oral dose is found 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 plasma elimination half-life (t1/2) of triclabendazole, the sulfoxide and sulfone metabolites in human is about 8, 14, and 11 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): 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): >8 gm/kg; Oral LD50 (mouse): >8 gm/kg A note on the use in pregnancy There are no available data on triclabendazole use in pregnant women to calculate a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Reproductive studies in animals (rat and rabbits) have not demonstrated an increased risk of increased fetal abnormalities with exposure to triclabendazole during the organogenesis period at doses which were about 0.3 to 1.6 times the maximum recommended human dose (MRHD) of 20 mg/kg. Carcinogenesis/Mutagenesis No genotoxic risk was noted for triclabendazole tested in 6 genotoxicity in vitro and in vivo assays. Impairment of Fertility No drug-related effects on reproductive performance, mating ratios or indices of fertility have been observed in a 2-generation reproductive and developmental toxicity study in rats. A note on use in breastfeeding There are no human findings on the presence of triclabendazole in milk, the effects on a nursing infant, or the effects on maternal milk production. The results of animal studies indicate that triclabendazole is found in goat milk when given as a single dose to a lactating female goat. When a drug is found to be present in animal milk, the likelihood that it will be found in human milk is high. Excercise caution if this drug is administered during nursing. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Egaten •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): Triclabendazole is an anthelmintic drug used to treat fascioliasis. 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 Trifluoperazine interact?

•Drug A: Adalimumab •Drug B: Trifluoperazine •Severity: MODERATE •Description: The metabolism of Trifluoperazine 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 anxiety disorders, depressive symptoms secondary to anxiety and agitation. •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): Trifluoperazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Trifluoperazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •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): Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •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): 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): 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): 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 agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and 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): Trifluoperazina Trifluoperazine Trifluopérazine Trifluoperazinum Trifluoroperazine Trifluperazine •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): Trifluoperazine is a phenothiazine used to treat depression, anxiety, and agitation.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Trifluoperazine interact? Information: •Drug A: Adalimumab •Drug B: Trifluoperazine •Severity: MODERATE •Description: The metabolism of Trifluoperazine 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 anxiety disorders, depressive symptoms secondary to anxiety and agitation. •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): Trifluoperazine is a trifluoro-methyl phenothiazine derivative intended for the management of schizophrenia and other psychotic disorders. Trifluoperazine has not been shown effective in the management of behaviorial complications in patients with mental retardation. •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): Trifluoperazine blocks postsynaptic mesolimbic dopaminergic D1 and D2 receptors in the brain; depresses the release of hypothalamic and hypophyseal hormones and is believed to depress the reticular activating system thus affecting basal metabolism, body temperature, wakefulness, vasomotor tone, and emesis. •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): 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): 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): 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 agitation, coma, convulsions, difficulty breathing, difficulty swallowing, dry mouth, extreme sleepiness, fever, intestinal blockage, irregular heart rate, low blood pressure, and 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): Trifluoperazina Trifluoperazine Trifluopérazine Trifluoperazinum Trifluoroperazine Trifluperazine •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): Trifluoperazine is a phenothiazine used to treat depression, anxiety, and agitation. 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 Trifluridine interact?

•Drug A: Adalimumab •Drug B: Trifluridine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Trifluridine. •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): As a standalone product, trifluridine is used for the ophthalmic treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. Trifluridine is also available as a combination product with tipiracil, which is indicated either alone or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted 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): Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo. Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro. While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials. In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines. The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA. Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice. In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo. In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo. Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec. •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 trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form. Subsequent phosphorylation produces trifluridine triphosphate, which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation. As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine. Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines. Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU). [A35289 However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells. •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 LONSURF with [14C]-trifluridine, at least 57% of the administered trifluridine was absorbed. Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumors, the mean times to peak plasma concentrations (T max ) of trifluridine was around 2 hours. Trifluridine area under the concentration-time curve from time 0 to the last measurable concentration (AUC 0-last ) was approximately 3-fold higher and maximum concentration (C max ) was approximately 2-fold higher after multiple dose administration (twice daily for 5 days a week with 2 days rest for 2 weeks followed by a 14-day rest, repeated every 4 weeks) than after single-dose administration. Following a single oral administration of LONSURF at 35 mg/m in patients with cancer, the mean time to peak plasma concentration (T max ) of trifluridine was around 2 hours. For the ophthalmic formulation, systemic absorption appears to be negligible. A standardized high-fat, high-calorie meal decreased trifluridine C max by approximately 40% but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m. In a dose finding study (15 to 35 mg/m twice daily), the AUC from time 0 to 10 hours (AUC0-10) of trifluridine tended to increase more than expected based on the increase in 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): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trifluridine is not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine. Other minor metabolites, such as 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea or 5-carboxyuraci, were also detected, but only at low or trace level in plasma and urine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After single oral administration of LONSURF (60 mg) with [14C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. The majority of recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours and the excretion into feces and expired air was <3% for both. The unchanged trifluridine was <3% of administered dose recovered in the 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): After administration of LONSURF 35 mg/m, the mean elimination and steady-state half-life (t 1/2 ) of trifluridine was 1.4 hours and 2.1 hours respectively. For the ophthalmic formulation, the half-life is significantly shorter, approximately only 12 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): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 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): Intravenous LD50 in rat was 2946 mg/kg. Oral LD50 in rat and mouse were > 4379mg/kg. Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications. Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lonsurf, Viroptic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trifluoromethyldeoxyuridine Trifluorothymidine Trifluorothymine deoxyriboside Trifluridin Trifluridina Trifluridine Trifluridinum •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): Trifluridine is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal 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 Trifluridine interact? Information: •Drug A: Adalimumab •Drug B: Trifluridine •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Trifluridine. •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): As a standalone product, trifluridine is used for the ophthalmic treatment of primay keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus, types 1 and 2. Trifluridine is also available as a combination product with tipiracil, which is indicated either alone or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. This combination product is also used for adult patients with metastatic gastric or gastroesophageal junction adenocarcinoma and were previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted 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): Trifluridine exhibits an antiviral effect against herpes simplex virus, types 1 and 2 and vacciniavirus both in vitro and in vivo. Some strains of adenovirus that contribute to the pathology of keratoconjunctivitis were shown to be susceptible to trifluridine in vitro. While there is evidence from a study that cross-resistance may develop between trifluridine and idoxuridine or vidarabine, trifluridine was shown to effective in treating dendritic ulcers in patients with herpetic keratitis who are unresponsive to idoxuridine or vidarabine based on the results from masked comparative trials. In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines. The cytotoxic activity of trifluridine and tipiracil against several human tumour xenografts show high correlation with the amount of trifluridine incorporated into DNA, indicating that the primary mechanism of action of trifluridine involves the direct incorporation into the cancer cell DNA. Trifluridine and tipiracil demonstrated anti-tumor activity against KRAS wild-type and mutant human colorectal cancer xenografts in mice. In clinical studies comprised of patients with previously treated metastatic colorectal cancer, treatment of trifluridine in combination with tipiracil in addition to best supportive care over a 5- or 7-month period resulted in increased progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) compared to placebo. In an open-label study, administration of trifluridine at the recommended dosage in patients with advanced solid tumors had no clinically relevant effect on QT/QTc prolongation compared with placebo. Two out of 48 patients displayed had QTc greater than 500 msec and 1 of 42 patients (2.4%) had a QTc increase from baseline greater than 60 msec. •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 trifluridine as an antiviral agent has not been fully elucidated, but appears to involve the inhibition of viral replication. Trifluridine gets incorporated into viral DNA during replication, which leads to the formation of defective proteins and an increased mutation rate. Trifluridine also mediates antineoplastic activities via this mechanism; following uptake into cancer cells, trifluridine is rapidly phosphorylated by thymidine kinase to its active monophosphate form. Subsequent phosphorylation produces trifluridine triphosphate, which is readily incorporated into the DNA of tumour cells in place of thymidine bases to perturb DNA function, DNA synthesis, and tumour cell proliferation. As trifluridine is subject to rapid degradation by TPase and readily metabolised by a first-pass effect following oral administration, tipiracil is added in the antineoplastic combination product as an inhibitor of TPase to increase the bioavailability of trifluridine. Trifluridine monophosphate also reversibly inhibits thymidylate synthetase (TS), an enzyme that is necessary for DNA synthesis and which levels are shown to be elevated different cancer cell lines. Up-regulation of the expression of the TS enzyme may also lead to the resistance to antineoplastic therapies, such as 5-fluorouracil (5-FU). [A35289 However, this inhibitory effect is not considered to be sufficient enough to fully contribute to the cytotoxicity in cancer cells. •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 LONSURF with [14C]-trifluridine, at least 57% of the administered trifluridine was absorbed. Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumors, the mean times to peak plasma concentrations (T max ) of trifluridine was around 2 hours. Trifluridine area under the concentration-time curve from time 0 to the last measurable concentration (AUC 0-last ) was approximately 3-fold higher and maximum concentration (C max ) was approximately 2-fold higher after multiple dose administration (twice daily for 5 days a week with 2 days rest for 2 weeks followed by a 14-day rest, repeated every 4 weeks) than after single-dose administration. Following a single oral administration of LONSURF at 35 mg/m in patients with cancer, the mean time to peak plasma concentration (T max ) of trifluridine was around 2 hours. For the ophthalmic formulation, systemic absorption appears to be negligible. A standardized high-fat, high-calorie meal decreased trifluridine C max by approximately 40% but did not change trifluridine AUC compared to those in a fasting state in patients with cancer following administration of a single dose of LONSURF 35 mg/m. In a dose finding study (15 to 35 mg/m twice daily), the AUC from time 0 to 10 hours (AUC0-10) of trifluridine tended to increase more than expected based on the increase in 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): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the apparent volume of distribution (Vd/F) for trifluridine was 21 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro findings suggest that the protein binding of trifluridine in human plasma is greater than 96%, where it is mainly bound to human serum albumin. Protein binding of trifluridine is independent of drug concentration and presence of tipiracil. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trifluridine is not metabolized by cytochrome P450 (CYP) enzymes. Trifluridine is mainly eliminated by metabolism via thymidine phosphorylase to form an inactive metabolite, 5-(trifluoromethyl) uracil (FTY). No other major metabolites were detected in plasma or urine. Other minor metabolites, such as 5-carboxy-2'-deoxyuridine found on the endothelial side of the cornea or 5-carboxyuraci, were also detected, but only at low or trace level in plasma and urine. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): After single oral administration of LONSURF (60 mg) with [14C]-trifluridine, the total cumulative excretion of radioactivity was 60% of the administered dose. The majority of recovered radioactivity was eliminated into urine (55% of the dose) as FTY and trifluridine glucuronide isomers within 24 hours and the excretion into feces and expired air was <3% for both. The unchanged trifluridine was <3% of administered dose recovered in the 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): After administration of LONSURF 35 mg/m, the mean elimination and steady-state half-life (t 1/2 ) of trifluridine was 1.4 hours and 2.1 hours respectively. For the ophthalmic formulation, the half-life is significantly shorter, approximately only 12 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): Following a single dose of LONSURF (35 mg/m ) in patients with advanced solid tumours, the oral clearance (CL/F) for trifluridine was 10.5 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): Intravenous LD50 in rat was 2946 mg/kg. Oral LD50 in rat and mouse were > 4379mg/kg. Overdosage via ocular instillation is unlikely. The highest dose of orally-administered Lonsurf, trifluridine in combination with tipiracil, administered in clinical studies was 180 mg/m^2 per day. The primary anticipated complication of an overdose is bone marrow suppression. There is no known antidote for trifluridine overdose: in case of an overdose, management should include customary therapeutic and supportive medical intervention aimed at correcting the presenting clinical manifestations and preventing their possible complications. Based on the findings from animal studies, trifluridine may cause fetal toxicity when administered to pregnant patients. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Lonsurf, Viroptic •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trifluoromethyldeoxyuridine Trifluorothymidine Trifluorothymine deoxyriboside Trifluridin Trifluridina Trifluridine Trifluridinum •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): Trifluridine is a nucleoside metabolic inhibitor used to treat keratoconjunctivitis and epithelial keratitis caused by simplex virus, and as a part of chemotherapy for certain types of metastatic gastrointestinal 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 Trimethoprim interact?

•Drug A: Adalimumab •Drug B: Trimethoprim •Severity: MODERATE •Description: The metabolism of Trimethoprim 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): As a monotherapy, trimethoprim is indicated for the treatment of acute episodes of uncomplicated urinary tract infections caused by susceptible bacteria, including E. coli., K. pneumoniae, Enterobacter spp., P. mirabilis, and coagulase-negative Staphylococcus species. In various formulations in combination with sulfamethoxazole, trimethoprim is indicated for the following infections caused by bacteria with documented susceptibility: urinary tract infections, acute otitis media in pediatric patients (when clinically indicated), acute exacerbations of chronic bronchitis in adults, enteritis caused by susceptible Shigella, prophylaxis and treatment of Pneumocystis jiroveci pneumonia, and travelers' diarrhea caused by enterotoxigenic E. coli. Trimethoprim is available as an ophthalmic solution in combination with polymyxin B for the treatment of acute bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis caused by susceptible bacteria. •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): Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative Staphylococcus species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. 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): Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal 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): Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C max ) are achieved within 1 to 4 hours (T max ) following the administration of a single 100mg dose. Trimethoprim appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/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): Trimethoprim is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Trimethoprim distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Trimethoprim is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Trimethoprim is 44% bound to plasma proteins, though the specific proteins to which it binds have not been elucidated. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trimethoprim undergoes oxidative metabolism to a number of metabolites, the most abundant of which are the demethylated 3'- and 4'- metabolites, accounting for approximately 65% and 25% of the total metabolite formation, respectively. Minor products include N-oxide metabolites (<5%) and benzylic metabolites in even smaller quantities. The parent drug is considered to be the therapeutically active form. The majority of trimethoprim biotransformation appears to involve CYP2C9 and CYP3A4 enzymes, with CYP1A2 contributing to a lesser extent. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is 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): Trimethoprim half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction. •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, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 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): The oral LD 50 in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively. Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bactrim, Polytrim, Primsol, Septra, Sulfatrim •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimethoprim Triméthoprime Trimethoprimum Trimetoprima •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): Trimethoprim is an antifolate antibiotic often used in combination with sulfamethoxazole to treat a number of infections, including those of the urinary tract, respiratory tract, and gastrointestinal tract.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Trimethoprim interact? Information: •Drug A: Adalimumab •Drug B: Trimethoprim •Severity: MODERATE •Description: The metabolism of Trimethoprim 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): As a monotherapy, trimethoprim is indicated for the treatment of acute episodes of uncomplicated urinary tract infections caused by susceptible bacteria, including E. coli., K. pneumoniae, Enterobacter spp., P. mirabilis, and coagulase-negative Staphylococcus species. In various formulations in combination with sulfamethoxazole, trimethoprim is indicated for the following infections caused by bacteria with documented susceptibility: urinary tract infections, acute otitis media in pediatric patients (when clinically indicated), acute exacerbations of chronic bronchitis in adults, enteritis caused by susceptible Shigella, prophylaxis and treatment of Pneumocystis jiroveci pneumonia, and travelers' diarrhea caused by enterotoxigenic E. coli. Trimethoprim is available as an ophthalmic solution in combination with polymyxin B for the treatment of acute bacterial conjunctivitis, blepharitis, and blepharoconjunctivitis caused by susceptible bacteria. •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): Trimethoprim exerts its antimicrobial effects by inhibiting an essential step in the synthesis of bacterial nucleic acids and proteins. It has shown activity against several species of gram-negative bacteria, as well as coagulase-negative Staphylococcus species. Resistance to trimethoprim may arise via a variety of mechanisms, including alterations to the bacterial cell wall, overproduction of dihydrofolate reductase, or production of resistant dihydrofolate reductase. Rarely, trimethoprim can precipitate the development of blood disorders (e.g. thrombocytopenia, leukopenia, etc.) which may be preceded by symptoms such as sore throat, fever, pallor, and or purpura - patients should be monitored closely for the development of these symptoms throught the course of therapy. 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): Trimethoprim is a reversible inhibitor of dihydrofolate reductase, one of the principal enzymes catalyzing the formation of tetrahydrofolic acid (THF) from dihydrofolic acid (DHF). Tetrahydrofolic acid is necessary for the biosynthesis of bacterial nucleic acids and proteins and ultimately for continued bacterial survival - inhibiting its synthesis, then, results in bactericidal activity. Trimethoprim binds with a much stronger affinity to bacterial dihydrofolate reductase as compared to its mammalian counterpart, allowing trimethoprim to selectively interfere with bacterial biosynthetic processes. Trimethoprim is often given in combination with sulfamethoxazole, which inhibits the preceding step in bacterial protein synthesis - given together, sulfamethoxazole and trimethoprim inhibit two consecutive steps in the biosynthesis of bacterial nucleic acids and proteins. As a monotherapy trimethoprim is considered bacteriostatic, but in combination with sulfamethoxazole is thought to exert bactericidal 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): Steady-state concentrations are achieved after approximately 3 days of repeat administration. Average peak serum concentrations of approximately 1 µg/mL (C max ) are achieved within 1 to 4 hours (T max ) following the administration of a single 100mg dose. Trimethoprim appears to follow first-order pharmacokinetics, as a single 200mg dose results in serum concentrations approximately double that of a 100mg dose. The steady-state AUC of orally administered trimethoprim is approximately 30 mg/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): Trimethoprim is extensively distributed into various tissues following oral administration. It distributes well into sputum, middle ear fluid, and bronchial secretions. Trimethoprim distributes efficiently into vaginal fluids, with observed concentrations approximately 1.6-fold higher than those seen in the serum. It may pass the placental barrier and into breast milk. Trimethoprim is also sufficiently excreted in the feces to markedly reduce and/or eliminate trimethoprim-susceptible fecal flora. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Trimethoprim is 44% bound to plasma proteins, though the specific proteins to which it binds have not been elucidated. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Trimethoprim undergoes oxidative metabolism to a number of metabolites, the most abundant of which are the demethylated 3'- and 4'- metabolites, accounting for approximately 65% and 25% of the total metabolite formation, respectively. Minor products include N-oxide metabolites (<5%) and benzylic metabolites in even smaller quantities. The parent drug is considered to be the therapeutically active form. The majority of trimethoprim biotransformation appears to involve CYP2C9 and CYP3A4 enzymes, with CYP1A2 contributing to a lesser extent. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Approximately 10-20% of an ingested trimethoprim dose is metabolized, primarily in the liver, while a large portion of the remainder is excreted unchanged in the urine. Following oral administration, 50% to 60% of trimethoprim is excreted in the urine within 24 hours, approximately 80% of which is 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): Trimethoprim half-life ranges from 8-10 hours, but may be prolonged in patients with renal dysfunction. •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, the renal clearance of trimethoprim has been variably reported between 51.7 - 91.3 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): The oral LD 50 in mice and rats is 2764 mg/kg and >5300 mg/kg, respectively. Prescribing information for trimethoprim states that signs of overdose may be evident following ingestion of doses >1 gram, and may include nausea, vomiting, dizziness, headaches, mental depression, confusion, and bone marrow depression. Treatment should consist of general supportive measures and gastric lavage, if applicable. Urinary acidification may increase renal elimination of trimethoprim. Hemodialysis is only moderately effective in eliminating trimethoprim and peritoneal dialysis is of no benefit. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bactrim, Polytrim, Primsol, Septra, Sulfatrim •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Trimethoprim Triméthoprime Trimethoprimum Trimetoprima •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): Trimethoprim is an antifolate antibiotic often used in combination with sulfamethoxazole to treat a number of infections, including those of the urinary tract, respiratory tract, and gastrointestinal tract. 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 Trimipramine interact?

•Drug A: Adalimumab •Drug B: Trimipramine •Severity: MAJOR •Description: The metabolism of Trimipramine 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 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 depression and depression accompanied by anxiety, agitation or sleep disturbance •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): Trimipramine is a tricyclic antidepressant. It was thought that tricyclic antidepressants work 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: a1 and b1 receptors are sensitized, a2 receptors are desensitised (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route. They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic. •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): Trimipramine's mechanism of action differs from other tricyclic antidepressants. Trimipramine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •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): Rapid 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): 93%-96% (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): 11-18 hrs •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): Side effects include agitation, coma, confusion, convulsions, dilated pupils, disturbed concentration, drowsiness, hallucinations, high fever, irregular heart rate, low body temperature, muscle rigidity, overactive reflexes, severely low blood pressure, stupor, vomiting •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): Trimeprimina Trimeprimine Trimeproprimine Trimipramina Trimipramine Trimipraminum •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): Trimipramine is a tricyclic antidepressant used to treat 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 with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Trimipramine interact? Information: •Drug A: Adalimumab •Drug B: Trimipramine •Severity: MAJOR •Description: The metabolism of Trimipramine 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 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 depression and depression accompanied by anxiety, agitation or sleep disturbance •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): Trimipramine is a tricyclic antidepressant. It was thought that tricyclic antidepressants work 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: a1 and b1 receptors are sensitized, a2 receptors are desensitised (leading to increased noradrenaline production). Tricyclics are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the CNS via an indirect serotonergic route. They are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic. •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): Trimipramine's mechanism of action differs from other tricyclic antidepressants. Trimipramine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT). •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): Rapid 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): 93%-96% (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): 11-18 hrs •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): Side effects include agitation, coma, confusion, convulsions, dilated pupils, disturbed concentration, drowsiness, hallucinations, high fever, irregular heart rate, low body temperature, muscle rigidity, overactive reflexes, severely low blood pressure, stupor, vomiting •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): Trimeprimina Trimeprimine Trimeproprimine Trimipramina Trimipramine Trimipraminum •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): Trimipramine is a tricyclic antidepressant used to treat 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 with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Tucatinib interact?

•Drug A: Adalimumab •Drug B: Tucatinib •Severity: MODERATE •Description: The metabolism of Tucatinib 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): Tucatinib is indicated with trastuzumab and capecitabine for the treatment of adults diagnosed with advanced unresectable or metastatic HER2-positive breast cancer. This includes patients with brain metastases and those who have received one or more prior anti-HER2-based regimens in the metastatic setting. It is also indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval; thus, it is 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): By inhibiting tyrosine kinase, tucatinib exerts anti-tumor activity, reducing the size of HER-2 positive breast cancer tumors. In clinical trials, the regimen of tucatinib and trastuzumab showed enhanced activity both in vitro and in vivo when compared to either drug administered by itself. •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): Mutations in the HER-2 gene are observed in some types of breast carcinoma. Tucatinib inhibits the tyrosine kinase enzyme of the HER-2 gene. Mutations of tyrosine kinase in the HER-2 gene lead to cascade effects of increased cell signaling and proliferation, resulting in malignancy. Results of in vitro studies show that tucatinib inhibits the phosphorylation of both HER-2 and HER-3, leading to downstream changes in MAPK and AKT signaling and cell proliferation. Anti-tumor activity occured in the cells that expressed HER-2. In vivo, tucatinib has been shown to inhibit HER-2 expressing tumors, likely by the same mechanism. •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 Tmax for tucatinib ranges from 1 to 4 hours. One pharmacokinetic study revealed a Cmax of 1120 ng/mL after a dose of 350 mg twice daily with a Tmax ranging from 1 to 3 hours. The AUCtau was reported to be about 7120 hours×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): The volume of distribution of tucatinib is about 1670 L. This drug penetrates the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tucatinib is about 97% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tucatinib is metabolized by CYP2C8 with some contributions from CYP3A. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): In a study of radiolabled tucatinib, about 86% of the total dose was excreted in the feces and 4.1% was found in the urine. About 16% of the tucatinib dose recovered in the feces was identified as unchanged tucatinib. •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): A pharmacokinetic study revealed a half-life of approximately 5.38 hours. Prescribing information mentions a geometric mean half-life of about 8.21 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 apparent clearance is 148 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): LD50 information and overdose information for tucatinib are not readily available in the literature. In the case of an overdose with this drug, increased adverse effects, such as diarrhea, nausea, abdominal pain, vomiting fatigue, hepatotoxicity, vomiting, decreased appetite, anemia, headache, and rash are expected. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tukysa •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): Tucatinib is a kinase inhibitor used to treat certain types of unresectable/metastatic HER-2 positive 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 CYP2C8 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Tucatinib interact? Information: •Drug A: Adalimumab •Drug B: Tucatinib •Severity: MODERATE •Description: The metabolism of Tucatinib 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): Tucatinib is indicated with trastuzumab and capecitabine for the treatment of adults diagnosed with advanced unresectable or metastatic HER2-positive breast cancer. This includes patients with brain metastases and those who have received one or more prior anti-HER2-based regimens in the metastatic setting. It is also indicated in combination with trastuzumab for the treatment of adult patients with RAS wild-type HER2-positive unresectable or metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. This indication is approved under accelerated approval; thus, it is 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): By inhibiting tyrosine kinase, tucatinib exerts anti-tumor activity, reducing the size of HER-2 positive breast cancer tumors. In clinical trials, the regimen of tucatinib and trastuzumab showed enhanced activity both in vitro and in vivo when compared to either drug administered by itself. •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): Mutations in the HER-2 gene are observed in some types of breast carcinoma. Tucatinib inhibits the tyrosine kinase enzyme of the HER-2 gene. Mutations of tyrosine kinase in the HER-2 gene lead to cascade effects of increased cell signaling and proliferation, resulting in malignancy. Results of in vitro studies show that tucatinib inhibits the phosphorylation of both HER-2 and HER-3, leading to downstream changes in MAPK and AKT signaling and cell proliferation. Anti-tumor activity occured in the cells that expressed HER-2. In vivo, tucatinib has been shown to inhibit HER-2 expressing tumors, likely by the same mechanism. •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 Tmax for tucatinib ranges from 1 to 4 hours. One pharmacokinetic study revealed a Cmax of 1120 ng/mL after a dose of 350 mg twice daily with a Tmax ranging from 1 to 3 hours. The AUCtau was reported to be about 7120 hours×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): The volume of distribution of tucatinib is about 1670 L. This drug penetrates the blood-brain barrier. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Tucatinib is about 97% bound to plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Tucatinib is metabolized by CYP2C8 with some contributions from CYP3A. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): In a study of radiolabled tucatinib, about 86% of the total dose was excreted in the feces and 4.1% was found in the urine. About 16% of the tucatinib dose recovered in the feces was identified as unchanged tucatinib. •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): A pharmacokinetic study revealed a half-life of approximately 5.38 hours. Prescribing information mentions a geometric mean half-life of about 8.21 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 apparent clearance is 148 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): LD50 information and overdose information for tucatinib are not readily available in the literature. In the case of an overdose with this drug, increased adverse effects, such as diarrhea, nausea, abdominal pain, vomiting fatigue, hepatotoxicity, vomiting, decreased appetite, anemia, headache, and rash are expected. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Tukysa •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): Tucatinib is a kinase inhibitor used to treat certain types of unresectable/metastatic HER-2 positive 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 CYP2C8 substrates. The severity of the interaction is moderate.

Does Adalimumab and Typhoid Vaccine Live interact?

•Drug A: Adalimumab •Drug B: Typhoid Vaccine Live •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Typhoid Vaccine Live. •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 Typhoid Vaccine Live interact? Information: •Drug A: Adalimumab •Drug B: Typhoid Vaccine Live •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Typhoid Vaccine Live. •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 Typhoid vaccine interact?

•Drug A: Adalimumab •Drug B: Typhoid vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Typhoid vaccine 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 Typhoid vaccine interact? Information: •Drug A: Adalimumab •Drug B: Typhoid vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Typhoid vaccine 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 Typhoid Vi polysaccharide vaccine interact?

•Drug A: Adalimumab •Drug B: Typhoid Vi polysaccharide vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Typhoid Vi polysaccharide vaccine 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 Typhoid Vi polysaccharide vaccine interact? Information: •Drug A: Adalimumab •Drug B: Typhoid Vi polysaccharide vaccine •Severity: MODERATE •Description: The therapeutic efficacy of Typhoid Vi polysaccharide vaccine 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 Ublituximab interact?

•Drug A: Adalimumab •Drug B: Ublituximab •Severity: MODERATE •Description: The risk or severity of infection can be increased when Ublituximab is combined with Adalimumab. •Extended Description: Prescribing information for Briumvi (ublituximab-xiiy) states that its co-administration with immunosuppressants (e.g. immunosuppressive doses of corticosteroids) may increase the risk of infection. Ublituximab, a B-cell depleting agent, is itself an immunosuppressive medication - the co-administration of ublituximab with agents exerting a similar effect may therefore result in additive immunosuppression and a subsequent increase in the risk of developing an infection. •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): Ublituximab is indicated in adult patients for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease by the FDA. It is also indicated by the EMA to treat relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. •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): Treatment with ublituximab reduces CD19+ B-cell counts - used as a surrogate marker for CD20+ B-cells due to ublituximab's interference with the CD20 assay - within 24 hours of the initial infusion. The median time for B-cell counts to return to either baseline or the lower limit of normal (LLN) was 70.3 weeks following the final infusion, and within 1.5 years of the final infusion approximately 58% of patients had returned to baseline or LLN. •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): B-cell dysregulation underlies the pathogenesis of various cancers and autoimmune conditions such as multiple sclerosis, neuromyelitis optica spectrum disease, and myelin oligodendrocyte glycoprotein IgG-associated disease. CD20 is an antigen expressed on pre-B cells, immature/mature B-cells, memory B-cells, and a subpopulation of CD3-positive T cells. Anti-CD20 antibodies can therefore induce B-cell depletion through direct cell death, induction of complement pathways, and Fc-gamma receptor (FcγR)-mediated phagocytosis (antibody-dependent cellular cytotoxicity, ADCC). Although several anti-CD20 antibodies have been developed, therapy has been hampered by low CD20 expression by malignant cells in diseases such as B-cell chronic lymphocytic leukemia and suboptimal antibody-dependent cytotoxicity. Ublituximab binds to an epitope on CD20 distinct from that bound by other approved antibodies such as rituximab, ofatumumab, obinutuzumab, and ocrelizumab, with a similar binding constant to rituximab. Uniquely, ublituximab is produced in the rat YB2/0 cell line such that it has a low fucose content (24% compared to 93% for rituximab ), improving its interaction with FcγR, especially FcγRIIIA (CD16) expressed by natural killer cells and macrophages. This difference grants ublituximab enhanced ADCC, including for low CD20-expressing malignant cells. The precise mechanism of action of ublituximab in the treatment of multiple sclerosis is unclear, but is presumed to involve CD20 binding and subsequent cell lysis as described above. •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 the administration of the approved recommended dosage of ublituximab, the geometric mean steady-state AUC was 3000 mcg/mL per day and the mean C max was 139 mcg/mL. In patients with relapsing multiple sclerosis, ublituximab exposure increases proportionally over a dose range of 150mg to 600mg. •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 central volume of distribution of ublituximab-xiiy was 3.18 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): As with other therapeutic proteins, the metabolism of ublituximab likely occurs via degradation to smaller peptides and amino acids by non-specific proteolytic 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): The estimated mean terminal half-life of ublituximab-xiiy was 22 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): 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): Briumvi •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): Ublituximab is a low-fucose CD20-targeted monoclonal antibody used in the treatment of relapsing forms of multiple sclerosis.

Prescribing information for Briumvi (ublituximab-xiiy) states that its co-administration with immunosuppressants (e.g. immunosuppressive doses of corticosteroids) may increase the risk of infection. Ublituximab, a B-cell depleting agent, is itself an immunosuppressive medication - the co-administration of ublituximab with agents exerting a similar effect may therefore result in additive immunosuppression and a subsequent increase in the risk of developing an infection. The severity of the interaction is moderate.

Question: Does Adalimumab and Ublituximab interact? Information: •Drug A: Adalimumab •Drug B: Ublituximab •Severity: MODERATE •Description: The risk or severity of infection can be increased when Ublituximab is combined with Adalimumab. •Extended Description: Prescribing information for Briumvi (ublituximab-xiiy) states that its co-administration with immunosuppressants (e.g. immunosuppressive doses of corticosteroids) may increase the risk of infection. Ublituximab, a B-cell depleting agent, is itself an immunosuppressive medication - the co-administration of ublituximab with agents exerting a similar effect may therefore result in additive immunosuppression and a subsequent increase in the risk of developing an infection. •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): Ublituximab is indicated in adult patients for the treatment of relapsing forms of multiple sclerosis (MS), including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease by the FDA. It is also indicated by the EMA to treat relapsing forms of multiple sclerosis (RMS) with active disease defined by clinical or imaging features. •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): Treatment with ublituximab reduces CD19+ B-cell counts - used as a surrogate marker for CD20+ B-cells due to ublituximab's interference with the CD20 assay - within 24 hours of the initial infusion. The median time for B-cell counts to return to either baseline or the lower limit of normal (LLN) was 70.3 weeks following the final infusion, and within 1.5 years of the final infusion approximately 58% of patients had returned to baseline or LLN. •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): B-cell dysregulation underlies the pathogenesis of various cancers and autoimmune conditions such as multiple sclerosis, neuromyelitis optica spectrum disease, and myelin oligodendrocyte glycoprotein IgG-associated disease. CD20 is an antigen expressed on pre-B cells, immature/mature B-cells, memory B-cells, and a subpopulation of CD3-positive T cells. Anti-CD20 antibodies can therefore induce B-cell depletion through direct cell death, induction of complement pathways, and Fc-gamma receptor (FcγR)-mediated phagocytosis (antibody-dependent cellular cytotoxicity, ADCC). Although several anti-CD20 antibodies have been developed, therapy has been hampered by low CD20 expression by malignant cells in diseases such as B-cell chronic lymphocytic leukemia and suboptimal antibody-dependent cytotoxicity. Ublituximab binds to an epitope on CD20 distinct from that bound by other approved antibodies such as rituximab, ofatumumab, obinutuzumab, and ocrelizumab, with a similar binding constant to rituximab. Uniquely, ublituximab is produced in the rat YB2/0 cell line such that it has a low fucose content (24% compared to 93% for rituximab ), improving its interaction with FcγR, especially FcγRIIIA (CD16) expressed by natural killer cells and macrophages. This difference grants ublituximab enhanced ADCC, including for low CD20-expressing malignant cells. The precise mechanism of action of ublituximab in the treatment of multiple sclerosis is unclear, but is presumed to involve CD20 binding and subsequent cell lysis as described above. •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 the administration of the approved recommended dosage of ublituximab, the geometric mean steady-state AUC was 3000 mcg/mL per day and the mean C max was 139 mcg/mL. In patients with relapsing multiple sclerosis, ublituximab exposure increases proportionally over a dose range of 150mg to 600mg. •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 central volume of distribution of ublituximab-xiiy was 3.18 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): As with other therapeutic proteins, the metabolism of ublituximab likely occurs via degradation to smaller peptides and amino acids by non-specific proteolytic 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): The estimated mean terminal half-life of ublituximab-xiiy was 22 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): 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): Briumvi •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): Ublituximab is a low-fucose CD20-targeted monoclonal antibody used in the treatment of relapsing forms of multiple sclerosis. Output: Prescribing information for Briumvi (ublituximab-xiiy) states that its co-administration with immunosuppressants (e.g. immunosuppressive doses of corticosteroids) may increase the risk of infection. Ublituximab, a B-cell depleting agent, is itself an immunosuppressive medication - the co-administration of ublituximab with agents exerting a similar effect may therefore result in additive immunosuppression and a subsequent increase in the risk of developing an infection. The severity of the interaction is moderate.

Does Adalimumab and Udenafil interact?

•Drug A: Adalimumab •Drug B: Udenafil •Severity: MODERATE •Description: The metabolism of Udenafil 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): Investigated for use/treatment in erectile dysfunction and 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): Udenafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor. •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): Udenafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by udenafil enhances erectile function by increasing the amount of cGMP. •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): Hepatic. Metabolized by CYP3A4 and CYP3A5. •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): 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): Udenafil is a PDE5 inhibitor used to treat erectile dysfunction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Udenafil interact? Information: •Drug A: Adalimumab •Drug B: Udenafil •Severity: MODERATE •Description: The metabolism of Udenafil 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): Investigated for use/treatment in erectile dysfunction and 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): Udenafil is a potent selective phosphodiesterase type 5 (PDE5) inhibitor. •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): Udenafil inhibits the cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cGMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The inhibition of phosphodiesterase type 5 (PDE5) by udenafil enhances erectile function by increasing the amount of cGMP. •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): Hepatic. Metabolized by CYP3A4 and CYP3A5. •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): 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): Udenafil is a PDE5 inhibitor used to treat erectile dysfunction. 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 Umeclidinium interact?

•Drug A: Adalimumab •Drug B: Umeclidinium •Severity: MODERATE •Description: The metabolism of Umeclidinium 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): Umeclidinium is approved by the FDA and Health Canada for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Additionally, umeclidinium also exists as combination products with vilanterol or vilanterol and fluticasone furoate. Both products were indicated for the maintenance treatment of COPD, but only the umeclidinium/ vilanterol / fluticasone furoate product was approved for the maintenance treatment of asthma in patients aged 18 years 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): QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent. In humans, the M3 receptor has been heavily implicated in the pathophysiology of asthma and COPD. Once the M3 receptor is activated, the phospholipase C would phosphorylate downstream targets, forming inositol 1,4,5-trisphosphate and eventually releasing intracellular Ca. Increase in intracellular Ca results in muscle contraction, thus worsening COPD and asthma-related bronchoconstriction. Additionally, M3 receptor activation also regulates pathways involving CD38, cyclic ADP ribose (cADPR), and ryanodine receptor channels, all of which control the intracellular Ca homeostasis that will lead to muscle contraction. •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): Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. •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): Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral 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): Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro plasma protein binding in human plasma was on average 89%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. •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 after once-daily inhaled dosing is 11 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): Plasma clearance following intravenous administration was 151 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): In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the maximum recommended human daily inhaled dose (MRHDID), respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species. In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day). Based on available data, no adjustment of the dosage of umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of umeclidinium included 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively). Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis). No human overdosage data has been reported with umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg of umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. Treatment of overdosage consists of discontinuation of INCRUSE ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. In clinical trials, the most common adverse effects of umeclidinium were nasopharyngitis, upper respiratory tract infection, cough, and arthralgia. Atrial fibrillation occurred in <1% of patients, but was more common among patients treated with umeclidinium than in those treated with placebo. Anticholinergics like umeclidinium should be used with caution in patients with narrow-angle glaucoma and in those with prostatic hyperplasia or bladder-neck obstruction. Inhaled medications can cause paradoxical bronchospasm, which can be fatal. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Anoro, Anoro Ellipta, Incruse Ellipta, Trelegy Ellipta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Umeclidinium •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): Umeclidinium is a long-acting muscarinic antagonist used as a long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD).

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Umeclidinium interact? Information: •Drug A: Adalimumab •Drug B: Umeclidinium •Severity: MODERATE •Description: The metabolism of Umeclidinium 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): Umeclidinium is approved by the FDA and Health Canada for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD). Additionally, umeclidinium also exists as combination products with vilanterol or vilanterol and fluticasone furoate. Both products were indicated for the maintenance treatment of COPD, but only the umeclidinium/ vilanterol / fluticasone furoate product was approved for the maintenance treatment of asthma in patients aged 18 years 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): QTc interval prolongation was studied in a double-blind, multiple-dose, placebo- and positive-controlled, crossover trial in 86 healthy subjects. Following repeat doses of umeclidinium 500 mcg once daily (8 times the recommended dosage) for 10 days, umeclidinium does not prolong QTc to any clinically relevant extent. In humans, the M3 receptor has been heavily implicated in the pathophysiology of asthma and COPD. Once the M3 receptor is activated, the phospholipase C would phosphorylate downstream targets, forming inositol 1,4,5-trisphosphate and eventually releasing intracellular Ca. Increase in intracellular Ca results in muscle contraction, thus worsening COPD and asthma-related bronchoconstriction. Additionally, M3 receptor activation also regulates pathways involving CD38, cyclic ADP ribose (cADPR), and ryanodine receptor channels, all of which control the intracellular Ca homeostasis that will lead to muscle contraction. •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): Umeclidinium is a long-acting muscarinic antagonist, which is often referred to as an anticholinergic. It has similar affinity to the subtypes of muscarinic receptors M1 to M5. In the airways, it exhibits pharmacological effects through inhibition of M3 receptors at the smooth muscle leading to bronchodilation. The competitive and reversible nature of antagonism was shown with human and animal origin receptors and isolated organ preparations. In preclinical in vitro as well as in vivo studies, prevention of methacholine- and acetylcholine-induced bronchoconstrictive effects was dose-dependent and lasted longer than 24 hours. The clinical relevance of these findings is unknown. The bronchodilation following inhalation of umeclidinium is predominantly a site-specific effect. •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): Umeclidinium plasma levels may not predict therapeutic effect. Following inhaled administration of umeclidinium in healthy subjects, C max occurred at 5 to 15 minutes. Umeclidinium is mostly absorbed from the lung after inhaled doses with minimum contribution from oral absorption. Following repeat dosing of inhaled umeclidinium, steady state was achieved within 14 days with 1.8-fold accumulation. The absolute bioavailability of inhaled umeclidinium was on average 13% of the dose, with negligible contribution from oral 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): Following intravenous administration to healthy subjects, the mean volume of distribution was 86 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): In vitro plasma protein binding in human plasma was on average 89%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): In vitro data showed that umeclidinium is primarily metabolized by the enzyme cytochrome P450 2D6 (CYP2D6) and is a substrate for the P-glycoprotein (P-gp) transporter. The primary metabolic routes for umeclidinium are oxidative (hydroxylation, O-dealkylation) followed by conjugation (e.g., glucuronidation), resulting in a range of metabolites with either reduced pharmacological activity or for which the pharmacological activity has not been established. Systemic exposure to the metabolites is low. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following intravenous dosing with radiolabeled umeclidinium, mass balance showed 58% of the radiolabel in the feces and 22% in the urine. The excretion of the drug-related material in the feces following intravenous dosing indicated elimination in the bile. Following oral dosing to healthy male subjects, radiolabel recovered in feces was 92% of the total dose and that in urine was <1% of the total dose, suggesting negligible oral absorption. •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 after once-daily inhaled dosing is 11 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): Plasma clearance following intravenous administration was 151 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): In separate embryofetal developmental studies, pregnant rats and rabbits received umeclidinium during the period of organogenesis at doses up to approximately 50 and 200 times the maximum recommended human daily inhaled dose (MRHDID), respectively (on an AUC basis at maternal inhalation doses up to 278 mcg/kg/day in rats and at maternal subcutaneous doses up to 180 mcg/kg/day in rabbits). No evidence of teratogenic effects was observed in either species. In a perinatal and postnatal developmental study in rats, dams received umeclidinium during late gestation and lactation periods with no evidence of effects on offspring development at doses up to approximately 26 times the MRHDID (on an AUC basis at maternal subcutaneous doses up to 60 mcg/kg/day). Based on available data, no adjustment of the dosage of umeclidinium in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of umeclidinium included 810 subjects aged 65 years and older, and, of those, 183 subjects were aged 75 years and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects. Umeclidinium produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 137 and 295/200 mcg/kg/day (male/female), respectively (approximately 20 and 25/20 times the MRHDID in adults on an AUC basis, respectively). Umeclidinium tested negative in the following genotoxicity assays: the in vitro Ames assay, in vitro mouse lymphoma assay, and in vivo rat bone marrow micronucleus assay. No evidence of impairment of fertility was observed in male and female rats at subcutaneous doses up to 180 mcg/kg/day and at inhaled doses up to 294 mcg/kg/day, respectively (approximately 100 and 50 times, respectively, the MRHDID in adults on an AUC basis). No human overdosage data has been reported with umeclidinium High doses of umeclidinium may lead to anticholinergic signs and symptoms. However, there were no systemic anticholinergic adverse effects following a once-daily inhaled dose of up to 1,000 mcg of umeclidinium (16 times the maximum recommended daily dose) for 14 days in subjects with COPD. Treatment of overdosage consists of discontinuation of INCRUSE ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. In clinical trials, the most common adverse effects of umeclidinium were nasopharyngitis, upper respiratory tract infection, cough, and arthralgia. Atrial fibrillation occurred in <1% of patients, but was more common among patients treated with umeclidinium than in those treated with placebo. Anticholinergics like umeclidinium should be used with caution in patients with narrow-angle glaucoma and in those with prostatic hyperplasia or bladder-neck obstruction. Inhaled medications can cause paradoxical bronchospasm, which can be fatal. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Anoro, Anoro Ellipta, Incruse Ellipta, Trelegy Ellipta •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Umeclidinium •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): Umeclidinium is a long-acting muscarinic antagonist used as a long-term maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD). 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 Upadacitinib interact?

•Drug A: Adalimumab •Drug B: Upadacitinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Upadacitinib. •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): Upadacitinib is indicated for the treatment of moderately to severely active rheumatoid arthritis or active psoriatic arthritis in adult patients who have had an inadequate response or intolerance to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as TNF blockers. In Europe, upadacitinib may be used as monotherapy or in combination with methotrexate for rheumatoid or psoriatic arthritis. Upadacitinib is indicated for use in patients 12 years of age and older with refractory, moderate-to-severe atopic dermatitis whose disease is inadequately controlled with other systemic therapies or when other therapies are inadvisable. Upadacitinib is indicated for the treatment of active ankylosing spondylitis or radiographic axial spondyloarthritis in adult patients who have an inadequate response to conventional therapy. It is also indicated to treat non-radiographic axial spondyloarthritis with objective signs of inflammation in adults who have had an inadequate response or intolerance to TNF blocker therapy. Upadacitinib is also indicated to treat moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to either conventional therapy or a biologic agent, such as to one or more TNF blockers. Upadacitinib is indicated to treat moderately to severely active Crohn’s disease in adults who have had an inadequate response or intolerance to one or more TNF blockers. Combining upadacitinib with other JAK inhibitors, biologic DMARDs, or other potent immunosuppressive agents is not recommended. •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): Upadacitinib is a DMARD that works by inhibiting the Janus Kinases (JAKs), which are essential downstream cell signalling mediators of pro-inflammatory cytokines. It is believed that these pro-inflammatory cytokines play a role in many autoimmune inflammatory conditions, such as rheumatoid arthritis. In clinical trials, upadacitinib decreased the activity of pro-inflammatory interleukins, transiently increased the levels of lymphocytes, and insignificantly decreased the levels of immunoglobulins from the baseline. •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): Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that involves the interplay of several mediators, including the immune cells (mainly T- and B-lymphocytes) and pro-inflammatory cytokines, such as the tumour necrosis factor (TNF), transforming growth factor (TGF), and interleukin 6 (IL-6). The Janus Kinase (JAK) family plays an essential role in the normal physiological functions (such as erythropoiesis), but also the signalling of pro-inflammatory cytokines that are implicated in many immune-mediated diseases. The JAK family consists of four isoforms (JAK1, JAK2, JAK3, and Tyrosine Kinase 2) that each interacts with different cytokine receptors and uniquely associates with the intracellular domains of Type I/II cytokine receptors. JAK1 is primarily involved in the signalling transduction pathways of IL-6, IFN and the common γ -chain cytokines, including IL-2 and IL-15. IL-6 has been closely studied in particular, as it is a major cytokine involved in B- and T-cell differentiation and the acute phase response in inflammation. Upon interaction of cytokines with their cytokine receptors, the JAKs mediate the JAK-STAT signal transduction pathway in response to receptor activation. JAKs are tyrosine kinases that cause phosphorylation of several proteins, including cytokine receptors and JAKs themselves. Phosphorylation of JAKs promotes the phosphorylation and activation of the signalling molecules called STATs, leading to their nuclear translocation, binding to DNA promoters, and target gene transcription. JAK1-mediated signalling pathways ultimately promote pro-inflammatory events, such as increased proliferation and survival of immune cells, T cell differentiation, and macrophage activation. Upadacitinib is a selective JAK1 inhibitor that has a negligible effect on JAK3, leading to an improved drug safety profile. Upadacitinib blocks the cellular processes that contribute to the inflammatory conditions in rheumatoid arthritis. In human leukocytes cellular assays, upadacitinib inhibited JAK1/3-induced phosphorylation of STAT3/5 mediated by IL-6/7. •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): Upadacitinib displays a dose-proportional pharmacokinetic profile over the therapeutic dose range. Following oral administration, the median time to reach Cmax (Tmax) ranges from 2 to 4 hours. The steady-state plasma concentrations of upadacitinib are reached within 4 days following multiple once-daily administrations, with minimal accumulation. Food intake has no clinically relevant effect on the AUC, Cmax, and Cmin of upadacitinib from the extended-release formulation. •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 upadacitinib in a patient with rheumatoid arthritis and a body weight of 74 kg is estimated to be 224 L following oral administration of an extended-release formula. In a pharmacokinetic study consisting of healthy volunteers receiving the extended-release formulation, the steady-state volume of distribution was 294 L. Upadacitinib partitions similarly between plasma and blood cellular components with a blood to plasma ratio of 1.0. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Upadacitinib is 52% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Upadacitinib predominantly undergoes CYP3A4-mediated metabolism; however, upadacitinib is a nonsensitive substrate of CYP3A4. It is also metabolized by CYP2D6 to a lesser extent. In a human radio-labelled study, about 79% of the total plasma radioactivity accounted for the parent drug, and about 13% of the total plasma radioactivity accounted for the main metabolite produced from mono-oxidation, followed by glucuronidation. There are no known active metabolites of upadacitinib. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following administration of a single radio-labelled dose from the immediate-release formulation, approximately 53% of the total dose was excreted in the feces where 38% of the excreted dose was an unchanged parent drug. About 43% of the total dose was excreted in the urine, where 24% of that dose was in the unchanged parent drug form. Approximately 34% of the total dose of upadacitinib dose was excreted 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 mean terminal elimination half-life of upadacitinib ranged from 8 to 14 hours following administration of the extended-release formulation. In clinical trials, approximately 90% of upadacitinib in the systemic circulation was eliminated within 24 hours of dosing. •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 upadacitinib in healthy volunteers receiving the extended-release formulation was 53.7 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): There is limited clinical information on the overdose from upacitinib: in clinical trials, once-daily administration of 60 mg in extended-release formulations were well tolerated. In case of an overdose, it is recommended that the patient is monitored for signs and symptoms of adverse reactions and treated with appropriate symptomatic treatment. The oral LD 50 in rats is 14500 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Rinvoq •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): Upadacitinib is an oral Janus kinase (JAK)1-selective inhibitor used in the treatment of moderate to severe rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, and severe atopic dermatitis, including in patients who did not respond well to other therapies.

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 Upadacitinib interact? Information: •Drug A: Adalimumab •Drug B: Upadacitinib •Severity: MAJOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Upadacitinib. •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): Upadacitinib is indicated for the treatment of moderately to severely active rheumatoid arthritis or active psoriatic arthritis in adult patients who have had an inadequate response or intolerance to one or more disease-modifying anti-rheumatic drugs (DMARDs), such as TNF blockers. In Europe, upadacitinib may be used as monotherapy or in combination with methotrexate for rheumatoid or psoriatic arthritis. Upadacitinib is indicated for use in patients 12 years of age and older with refractory, moderate-to-severe atopic dermatitis whose disease is inadequately controlled with other systemic therapies or when other therapies are inadvisable. Upadacitinib is indicated for the treatment of active ankylosing spondylitis or radiographic axial spondyloarthritis in adult patients who have an inadequate response to conventional therapy. It is also indicated to treat non-radiographic axial spondyloarthritis with objective signs of inflammation in adults who have had an inadequate response or intolerance to TNF blocker therapy. Upadacitinib is also indicated to treat moderately to severely active ulcerative colitis in adults who have had an inadequate response or intolerance to either conventional therapy or a biologic agent, such as to one or more TNF blockers. Upadacitinib is indicated to treat moderately to severely active Crohn’s disease in adults who have had an inadequate response or intolerance to one or more TNF blockers. Combining upadacitinib with other JAK inhibitors, biologic DMARDs, or other potent immunosuppressive agents is not recommended. •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): Upadacitinib is a DMARD that works by inhibiting the Janus Kinases (JAKs), which are essential downstream cell signalling mediators of pro-inflammatory cytokines. It is believed that these pro-inflammatory cytokines play a role in many autoimmune inflammatory conditions, such as rheumatoid arthritis. In clinical trials, upadacitinib decreased the activity of pro-inflammatory interleukins, transiently increased the levels of lymphocytes, and insignificantly decreased the levels of immunoglobulins from the baseline. •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): Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that involves the interplay of several mediators, including the immune cells (mainly T- and B-lymphocytes) and pro-inflammatory cytokines, such as the tumour necrosis factor (TNF), transforming growth factor (TGF), and interleukin 6 (IL-6). The Janus Kinase (JAK) family plays an essential role in the normal physiological functions (such as erythropoiesis), but also the signalling of pro-inflammatory cytokines that are implicated in many immune-mediated diseases. The JAK family consists of four isoforms (JAK1, JAK2, JAK3, and Tyrosine Kinase 2) that each interacts with different cytokine receptors and uniquely associates with the intracellular domains of Type I/II cytokine receptors. JAK1 is primarily involved in the signalling transduction pathways of IL-6, IFN and the common γ -chain cytokines, including IL-2 and IL-15. IL-6 has been closely studied in particular, as it is a major cytokine involved in B- and T-cell differentiation and the acute phase response in inflammation. Upon interaction of cytokines with their cytokine receptors, the JAKs mediate the JAK-STAT signal transduction pathway in response to receptor activation. JAKs are tyrosine kinases that cause phosphorylation of several proteins, including cytokine receptors and JAKs themselves. Phosphorylation of JAKs promotes the phosphorylation and activation of the signalling molecules called STATs, leading to their nuclear translocation, binding to DNA promoters, and target gene transcription. JAK1-mediated signalling pathways ultimately promote pro-inflammatory events, such as increased proliferation and survival of immune cells, T cell differentiation, and macrophage activation. Upadacitinib is a selective JAK1 inhibitor that has a negligible effect on JAK3, leading to an improved drug safety profile. Upadacitinib blocks the cellular processes that contribute to the inflammatory conditions in rheumatoid arthritis. In human leukocytes cellular assays, upadacitinib inhibited JAK1/3-induced phosphorylation of STAT3/5 mediated by IL-6/7. •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): Upadacitinib displays a dose-proportional pharmacokinetic profile over the therapeutic dose range. Following oral administration, the median time to reach Cmax (Tmax) ranges from 2 to 4 hours. The steady-state plasma concentrations of upadacitinib are reached within 4 days following multiple once-daily administrations, with minimal accumulation. Food intake has no clinically relevant effect on the AUC, Cmax, and Cmin of upadacitinib from the extended-release formulation. •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 upadacitinib in a patient with rheumatoid arthritis and a body weight of 74 kg is estimated to be 224 L following oral administration of an extended-release formula. In a pharmacokinetic study consisting of healthy volunteers receiving the extended-release formulation, the steady-state volume of distribution was 294 L. Upadacitinib partitions similarly between plasma and blood cellular components with a blood to plasma ratio of 1.0. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Upadacitinib is 52% bound to human plasma proteins. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Upadacitinib predominantly undergoes CYP3A4-mediated metabolism; however, upadacitinib is a nonsensitive substrate of CYP3A4. It is also metabolized by CYP2D6 to a lesser extent. In a human radio-labelled study, about 79% of the total plasma radioactivity accounted for the parent drug, and about 13% of the total plasma radioactivity accounted for the main metabolite produced from mono-oxidation, followed by glucuronidation. There are no known active metabolites of upadacitinib. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following administration of a single radio-labelled dose from the immediate-release formulation, approximately 53% of the total dose was excreted in the feces where 38% of the excreted dose was an unchanged parent drug. About 43% of the total dose was excreted in the urine, where 24% of that dose was in the unchanged parent drug form. Approximately 34% of the total dose of upadacitinib dose was excreted 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 mean terminal elimination half-life of upadacitinib ranged from 8 to 14 hours following administration of the extended-release formulation. In clinical trials, approximately 90% of upadacitinib in the systemic circulation was eliminated within 24 hours of dosing. •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 upadacitinib in healthy volunteers receiving the extended-release formulation was 53.7 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): There is limited clinical information on the overdose from upacitinib: in clinical trials, once-daily administration of 60 mg in extended-release formulations were well tolerated. In case of an overdose, it is recommended that the patient is monitored for signs and symptoms of adverse reactions and treated with appropriate symptomatic treatment. The oral LD 50 in rats is 14500 mg/kg. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Rinvoq •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): Upadacitinib is an oral Janus kinase (JAK)1-selective inhibitor used in the treatment of moderate to severe rheumatoid arthritis, active psoriatic arthritis, ankylosing spondylitis, and severe atopic dermatitis, including in patients who did not respond well to other therapies. 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 Ustekinumab interact?

•Drug A: Adalimumab •Drug B: Ustekinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Ustekinumab. •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): Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in patients 6 years of age and older who are candidates for phototherapy or systemic therapy. In adult patients, it is also indicated for the management of active psoriatic arthritis (PsA) alone or in combination with methotrexate, moderately to severely active Crohn’s disease (CD) and moderately to severely active ulcerative colitis. •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): Ustekinumab is a targeted antibody therapy that suppresses immune responses. It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions. It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8. The formation of cytochrome P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation. Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity. While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs, there were no clinically significant effects on human CYP enzyme activities. The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis. •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): Interleukin (IL)-12 and IL-23 are heterodimeric cytokines that evoke immune and inflammatory responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. The role of IL-12 and IL-23 were implicated in a variety of chronic inflammatory conditions, such as psoriasis and inflammatory bowel diseases. They modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets, as CD4+ T cells can differentiate into T-helper (Th) effector lineages based on the environment. Th cells can further activate the downstream pro-inflammatory mediators and transcription factors such as TNFα and IFNγ that drive innate and adaptive immunity. IL-12 and IL-23 share a common p40 subunit, paired with p35 and p19 subunits of IL-12 and IL-23, respectively. The antigen-binding fragment (Fab) of ustekinumab binds the D1 domain of the p40 subunit of IL-12 and IL-23 in a 1:1 ratio. This prevents IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of NK and T cells. Ustekinumab only binds to IL-12 and IL-23 that are unbound to IL-12Rβ1, so it is unlikely to initiate Fc effector functions, such as ADCC or CDC. Inhibition of the IL-12/23 signalling pathway leads to profound suppression of both the Th1 and Th17 cell lineage of cytokines and chemokines and their inflammatory 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): The median Tmax following a single subcutaneous dose administration of 45mg and 90mg in adults with psoriasis was 13.5 days and 7 days, respectively. The median Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45mg and 90mg, respectively. The median AUC was 84.9 μg·day/mL and 226.9 μg·day/mL, respectively. Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn’s disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis. The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis. The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%. •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 total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis. The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76 to 161 mL/kg in patients with psoriasis receiving a single subcutaneous dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information on plasma protein binding of ustekinumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolic pathway of ustekinumab has not been fully characterized; it is expected to undergo nonspecific protein degradation via catabolic pathways in the same manner as endogenous IgG. •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 on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation. •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 administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively. The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis. •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 apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7 to 5.3 mL/day/kg. In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis. •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 dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials. Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Stelara •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): Ustekinumab is a targeted antibody therapy used to manage inflammatory conditions such as plaque psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis.

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 Ustekinumab interact? Information: •Drug A: Adalimumab •Drug B: Ustekinumab •Severity: MINOR •Description: The risk or severity of adverse effects can be increased when Adalimumab is combined with Ustekinumab. •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): Ustekinumab is indicated for the management of moderate to severe plaque psoriasis in patients 6 years of age and older who are candidates for phototherapy or systemic therapy. In adult patients, it is also indicated for the management of active psoriatic arthritis (PsA) alone or in combination with methotrexate, moderately to severely active Crohn’s disease (CD) and moderately to severely active ulcerative colitis. •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): Ustekinumab is a targeted antibody therapy that suppresses immune responses. It acts by reducing the signaling pathways of pro-inflammatory cytokines IL-12 and IL-23, which play a role in various inflammatory conditions. It downregulates the gene expression of inflammatory cytokines and chemokines such as MCP-1, TNF-alpha, IP-10, and IL-8. The formation of cytochrome P-450 enzymes may be altered by elevated levels of certain cytokines during chronic inflammation. Research shows that there is an inverse relationship between plasma levels of inflammatory cytokines and CYP450 enzyme formation and activity. While ustekinumab may potentially normalize the formation of CYP enzymes and enhance the CYP-mediated metabolism of drugs, there were no clinically significant effects on human CYP enzyme activities. The steady-state was achieved by 28 weeks after multiple subcutaneous dose administration in adult patients with psoriasis. •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): Interleukin (IL)-12 and IL-23 are heterodimeric cytokines that evoke immune and inflammatory responses, such as natural killer cell activation and CD4+ T-cell differentiation and activation. The role of IL-12 and IL-23 were implicated in a variety of chronic inflammatory conditions, such as psoriasis and inflammatory bowel diseases. They modulate lymphocyte function, including T-helper (Th) 1 and Th17 cell subsets, as CD4+ T cells can differentiate into T-helper (Th) effector lineages based on the environment. Th cells can further activate the downstream pro-inflammatory mediators and transcription factors such as TNFα and IFNγ that drive innate and adaptive immunity. IL-12 and IL-23 share a common p40 subunit, paired with p35 and p19 subunits of IL-12 and IL-23, respectively. The antigen-binding fragment (Fab) of ustekinumab binds the D1 domain of the p40 subunit of IL-12 and IL-23 in a 1:1 ratio. This prevents IL-12 and IL-23 from binding to the IL-12Rβ1 receptor chain of IL-12 (IL-12Rβ1/β2) and IL-23 (IL-12Rβ1/23R) receptor complexes on the surface of NK and T cells. Ustekinumab only binds to IL-12 and IL-23 that are unbound to IL-12Rβ1, so it is unlikely to initiate Fc effector functions, such as ADCC or CDC. Inhibition of the IL-12/23 signalling pathway leads to profound suppression of both the Th1 and Th17 cell lineage of cytokines and chemokines and their inflammatory 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): The median Tmax following a single subcutaneous dose administration of 45mg and 90mg in adults with psoriasis was 13.5 days and 7 days, respectively. The median Cmax in the same group of patients was 2.4 μg/mL and 5.3 μg/mL at doses of 45mg and 90mg, respectively. The median AUC was 84.9 μg·day/mL and 226.9 μg·day/mL, respectively. Following an intravenous induction dose administration, the mean ± SD Cmax was 125.2 ± 33.6 mcg/mL in patients with Crohn’s disease and 129.1 ± 27.6 mcg/mL in patients with ulcerative colitis. The systemic exposure of ustekinumab (Cmax and AUC) increases in a linear or dose-proportional manner following a single subcutaneous administration at doses ranging from approximately 24 mg to 240 mg in patients with psoriasis. The estimated absolute bioavailability (F) of ustekinumab following a single subcutaneous dose administration in patients with psoriasis is 57.2%. •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 total volume of distribution at steady-state was 4.62 L in patients with Crohn’s disease and 4.4 L in patients with ulcerative colitis. The median apparent volume of distribution during the terminal phase (Vz/F) ranged from 76 to 161 mL/kg in patients with psoriasis receiving a single subcutaneous dose. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): There is no information on plasma protein binding of ustekinumab. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): The metabolic pathway of ustekinumab has not been fully characterized; it is expected to undergo nonspecific protein degradation via catabolic pathways in the same manner as endogenous IgG. •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 on the main route of elimination of ustekinumab; it is expected to undergo renal excretion following degradation. •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 administration of a single subcutaneous dose of 45 mg or 90 mg in patients with psoriasis, the median half-life was 19.8 days and 21.2, respectively. The estimated median terminal half-life of approximately 19 days in patients with Crohn’s disease or ulcerative colitis. •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 apparent clearance (CL/F) following a single subcutaneous administration to patients with psoriasis ranged from 2.7 to 5.3 mL/day/kg. In patients with Crohn’s disease, the clearance was 0.19 L/day in patients with Crohn’s disease or ulcerative colitis. •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 dose-limiting toxicity were not observed with intravenous administration of single doses up to 6 mg/kg in clinical trials. Information on overdose of ustekinumab is limited: in the event of overdose, patients should be monitored for any signs and symptoms of drug-related adverse events and appropriate symptomatic treatment should be initiated. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Stelara •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): Ustekinumab is a targeted antibody therapy used to manage inflammatory conditions such as plaque psoriasis, psoriatic arthritis, Crohn's Disease, and ulcerative colitis. 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 Valbenazine interact?

•Drug A: Adalimumab •Drug B: Valbenazine •Severity: MODERATE •Description: The metabolism of Valbenazine 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): Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s 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): Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile. Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec. •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 valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. •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): Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (C max ) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose). Following oral administration, the time to reach maximum valbenazine plasma concentration (T max ) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches C max 4 to 8 hours after administration of valbenazine. Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected. •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 mean steady-state volume of distribution of valbenazine is 92 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or 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): Both Valbenazine and [+]-α-HTBZ have half-lives of 15 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): Valbenazine has a mean total plasma systemic clearance value of 7.2 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 limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m. Advise a pregnant woman of the potential risk to a fetus. In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m, respectively. Valbenazine delayed mating in both sexes, which led to a lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function. Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m. Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30, and 75 mg/kg/day, which are 0.6, 1.9, and 4.6 times the MRHD of 80 mg/day based on mg/m. Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ingrezza •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): Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia and chorea associated with Huntington'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 CYP2D6 substrates. The severity of the interaction is moderate.

Question: Does Adalimumab and Valbenazine interact? Information: •Drug A: Adalimumab •Drug B: Valbenazine •Severity: MODERATE •Description: The metabolism of Valbenazine 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): Valbenazine is indicated for the treatment of adults with tardive dyskinesia and chorea associated with Huntington’s 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): Valbenazine inhibits human VMAT2 (Ki ~ 150 nM) with no appreciable binding affinity for VMAT1 (Ki > 10 µM). Valbenazine is converted to the active metabolite [+]-α-dihydrotetrabenazine ([+]-α-HTBZ). [+]-α-HTBZ also binds with relatively high affinity to human VMAT2 (Ki ~ 3 nM). Valbenazine and [+]-αHTBZ have no appreciable binding affinity (Ki > 5000 nM) for dopaminergic (including D2), serotonergic (including 5HT2B), adrenergic, histaminergic or muscarinic receptors, thus limiting off-target receptors binding for a more favorable safety profile. Valbenazine may cause an increase in the corrected QT interval in patients who are CYP2D6-poor metabolizers or who are taking a strong CYP2D6 or CYP3A4 inhibitor. An exposure-response analysis of clinical data from two healthy volunteer studies revealed increased QTc interval with higher plasma concentrations of the active metabolite. Based on this model, patients taking an valbenazine 60 mg or 80 mg dose with increased exposure to the metabolite (e.g., being a CYP2D6 poor metabolizer) may have a mean (upper bound of double-sided 90% CI) QT prolongation of 9.6 (12.0) msec or 11.7 (14.7) msec, respectively as compared to otherwise healthy volunteers given valbenazine, who had a respective mean (upper bound of double-sided 90% CI) QT prolongation of 5.3 (6.7) msec or 6.7 (8.4) msec. •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 valbenzine is still unknown, it is thought be mediated through the reversible inhibition of vesicular monoamine transporter 2 (VMAT2), a transporter that regulates monoamine uptake from the cytoplasm to the synaptic vesicle for storage and release. •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): Valbenazine and its active metabolite ([+]-α-HTBZ) demonstrate approximate proportional increases for the area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (C max ) after single oral doses from 40 mg to 300 mg (i.e., 50% to 375% of the recommended treatment dose). Following oral administration, the time to reach maximum valbenazine plasma concentration (T max ) ranges from 0.5 to 1.0 hours. Valbenazine reaches steady-state plasma concentrations within 1 week. The absolute oral bioavailability of valbenazine is approximately 49%. [+]-α-HTBZ gradually forms and reaches C max 4 to 8 hours after administration of valbenazine. Ingestion of a high-fat meal decreases valbenazine Cmax by approximately 47% and AUC by approximately 13%. [+]-α-HTBZ Cmax and AUC are unaffected. •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 mean steady-state volume of distribution of valbenazine is 92 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): The plasma protein binding of valbenazine and [+]-α-HTBZ is greater than 99% and approximately 64%, respectively. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Valbenazine is extensively metabolized after oral administration by hydrolysis of the valine ester to form the active metabolite ([+]-α-HTBZ) and by oxidative metabolism, primarily by CYP3A4/5, to form mono-oxidized valbenazine and other minor metabolites. [+]-α-HTBZ appears to be further metabolized in part by CYP2D6. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Following the administration of a single 50-mg oral dose of radiolabeled C-valbenazine (i.e., ~63% of the recommended treatment dose), approximately 60% and 30% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 2% was excreted as unchanged valbenazine or [+]-α-HTBZ in either urine or 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): Both Valbenazine and [+]-α-HTBZ have half-lives of 15 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): Valbenazine has a mean total plasma systemic clearance value of 7.2 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 limited available data on valbenazine use in pregnant women are insufficient to inform a drug-associated risk. In animal reproductive studies, no malformations were observed when valbenazine was administered orally to rats and rabbits during the period of organogenesis at doses up to 1.8 or 24 times, respectively, the maximum recommended human dose (MRHD) of 80 mg/day based on mg/m2 body surface area. However, administration of valbenazine to pregnant rats during organogenesis through lactation produced an increase in the number of stillborn pups and postnatal pup mortalities at doses <1 times the MRHD based on mg/m. Advise a pregnant woman of the potential risk to a fetus. In a fertility study, rats were treated orally with valbenazine at 1, 3, and 10 mg/kg/day prior to mating and through mating, for a minimum of 10 weeks (males) or through Day 7 of gestation (females). These doses are 0.1, 0.4, and 1.2 times the MRHD of 80 mg/day based on mg/m, respectively. Valbenazine delayed mating in both sexes, which led to a lower number of pregnancies and disrupted estrous cyclicity at the high dose, 1.2 times the MRHD of 80 mg/day based on mg/m. Valbenazine had no effects on sperm parameters (motility, count, density) or on uterine parameters (corpora lutea, number of implants, viable implants, pre-implantation loss, early resorptions, and post-implantation loss) at any dose. Patients with moderate to severe hepatic impairment (Child-Pugh score 7 to 15) had higher exposure of valbenazine and its active metabolite than patients with normal hepatic function. Valbenazine did not increase tumors in rats treated orally for 91 weeks at 0.5, 1, and 2 mg/kg/day. These doses are <1 times (0.06, 0.1, and 0.24 times, respectively) the MRHD of 80 mg/day based on mg/m. Valbenazine did not increase tumors in hemizygous Tg.rasH2 mice treated orally for 26 weeks at 10, 30, and 75 mg/kg/day, which are 0.6, 1.9, and 4.6 times the MRHD of 80 mg/day based on mg/m. Valbenazine was not mutagenic in the in vitro bacterial reverse mutation test (Ames) or clastogenic in the in vitro mammalian chromosomal aberrations assay in human peripheral blood lymphocytes or in the in vivo rat bone marrow micronucleus assay. No specific antidotes for valbenazine are known. In managing overdose, provide supportive care, including close medical supervision and monitoring, and consider the possibility of multiple drug involvement. If an overdose occurs, consult a Certified Poison Control Center. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Ingrezza •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): Valbenazine is a vesicular monoamine transporter 2 inhibitor used to treat tardive dyskinesia and chorea associated with Huntington'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 CYP2D6 substrates. The severity of the interaction is moderate.

Does Adalimumab and Valdecoxib interact?

•Drug A: Adalimumab •Drug B: Valdecoxib •Severity: MODERATE •Description: The metabolism of Valdecoxib 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 of osteoarthritis and dysmenorrhoea •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): Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. •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): Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit 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): Oral bioavailability is 83%. •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): 86 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic (involves CYP3A4 and 2C9) •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-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): 8-11 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): oral cl=6 L/h 6 – 7 L/h [In patients undergoing hemodialysis] 6 – 7 L/h [healthy elderly subjects] •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 following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bextra •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): Valdecoxib is a COX-2 inhibitor used to treat osteoarthritis and dysmenorrhoea.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Valdecoxib interact? Information: •Drug A: Adalimumab •Drug B: Valdecoxib •Severity: MODERATE •Description: The metabolism of Valdecoxib 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 of osteoarthritis and dysmenorrhoea •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): Valdecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is classified as a nonsteroidal anti-inflammatory drug (NSAID). Valdecoxib is used for its anti-inflammatory, analgesic, and antipyretic activities in the management of osteoarthritis (OA) and for the treatment of dysmenorrhea or acute pain. Unlike celecoxib, valdecoxib lacks a sulfonamide chain and does not require CYP450 enzymes for metabolism. •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): Both COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostaglandin (PG) H2, the precursor of PGs and thromboxane. Valdecoxib selectively inhibits the cyclooxygenase-2 (COX-2) enzyme, important for the mediation of inflammation and pain. Unlike non-selective NSAIDs, valdecoxib does not inhibit 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): Oral bioavailability is 83%. •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): 86 L •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): 98% •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Hepatic (involves CYP3A4 and 2C9) •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Valdecoxib is eliminated predominantly via hepatic metabolism with less than 5% of the dose excreted unchanged in the urine and feces. About 70% of the dose is excreted in the urine as metabolites, and about 20% as valdecoxib N-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): 8-11 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): oral cl=6 L/h 6 – 7 L/h [In patients undergoing hemodialysis] 6 – 7 L/h [healthy elderly subjects] •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 following acute NSAID overdoses are usually limited to lethargy, drowsiness, nausea, vomiting, and epigastric pain, which are generally reversible with supportive care. Gastrointestinal bleeding can occur. Hypertension, acute renal failure, respiratory depression and coma may occur, but are rare. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Bextra •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): Valdecoxib is a COX-2 inhibitor used to treat osteoarthritis and dysmenorrhoea. 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 Valproic acid interact?

•Drug A: Adalimumab •Drug B: Valproic acid •Severity: MODERATE •Description: The metabolism of Valproic acid 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): Indicated for: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. •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): Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate 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 exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective 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 intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%. •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): 11 L/1.73m. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% 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): 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 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): 0.56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. •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 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Depakene, Depakote, Epival •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): acide valproïque ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure •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): Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Valproic acid interact? Information: •Drug A: Adalimumab •Drug B: Valproic acid •Severity: MODERATE •Description: The metabolism of Valproic acid 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): Indicated for: 1) Use as monotherapy or adjunctive therapy in the management of complex partial seizures and simple or complex absence seizures. 2) Adjunctive therapy in the management of multiple seizure types that include absence seizures. 3) Prophylaxis of migraine headaches. 4) Acute management of mania associated with bipolar disorder. Off-label uses include: 1) Maintenance therapy for bipolar disorder. 2) Treatment for acute bipolar depression. 3) Emergency treatment of status epilepticus. •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): Valproate has been shown to reduce the incidence of complex partial seizures and migraine headaches. It also improves symptom control in bipolar mania. Although the exact mechanisms responsible are unknown, it is thought that valproate produces increased cortical inhibition to contribute to control of neural synchrony. It is also thought that valproate exerts a neuroprotective effect preventing damage and neural degeneration in epilepsy, migraines, and bipolar disorder. Valproate is hepatotoxic and teratogenic. The reasons for this are unclear but have been attributed to the genomic effects of the drug. A small proof-of concept study found that valproate increases clearance of human immunodeficiency virus (HIV) when combined with highly active antiretroviral therapy (HAART) by reactivating the virus to allow clearance, however, a larger multicentre trial failed to show a significant effect on HIV reservoirs when added to HAART. The FDA labeling contains a warning regarding HIV reactivation during valproate 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 exact mechanisms by which valproate exerts it's effects on epilepsy, migraine headaches, and bipolar disorder are unknown however several pathways exist which may contribute to the drug's action. Valproate is known to inhibit succinic semialdehyde dehydrogenase. This inhibition results in an increase in succinic semialdehyde which acts as an inhibitor of GABA transaminase ultimately reducing GABA metabolism and increasing GABAergic neurotransmission. As GABA is an inhibitory neurotransmitter, this increase results in increased inhibitory activity. A possible secondary contributor to cortical inhibition is a direct suppression of voltage gated sodium channel activity and indirect suppression through effects on GABA. It has also been suggested that valproate impacts the extracellular signal-related kinase pathway (ERK). These effects appear to be dependent on mitogen-activated protein kinase (MEK) and result in the phosphorylation of ERK1/2. This activation increases expression of several downstream targets including ELK-1 with subsequent increases in c-fos, growth cone-associated protein-43 which contributes to neural plasticity, B-cell lymphoma/leukaemia-2 which is an anti-apoptotic protein, and brain-derived neurotrophic factor (BDNF) which is also involved in neural plasticity and growth. Increased neurogenesis and neurite growth due to valproate are attributed to the effects of this pathway. An additional downstream effect of increased BDNF expression appears to be an increase in GABA A receptors which contribute further to increased GABAergic activity. Valproate exerts a non-competitive indirect inhibitory effect on myo-inosital-1-phophate synthetase. This results in reduced de novo synthesis of inositol monophosphatase and subsequent inositol depletion. It is unknown how this contributed to valproate's effects on bipolar disorder but [lithium] is known to exert a similar inositol-depleting effect. Valproate exposure also appears to produce down-regulation of protein kinase C proteins (PKC)-α and -ε which are potentially related to bipolar disorder as PKC is unregulated in the frontal cortex of bipolar patients. This is further supported by a similar reduction in PKC with lithium. The inhibition of the PKC pathway may also be a contributor to migraine prophylaxis. Myristoylated alanine-rich C kinase substrate, a PKC substrate, is also downregulated by valproate and may contribute to changes in synaptic remodeling through effects on the cytoskeleton. Valproate also appears to impact fatty acid metabolism. Less incorporation of fatty acid substrates in sterols and glycerolipids is thought to impact membrane fluidity and result in increased action potential threshold potentially contributing to valproate's antiepileptic action. Valproate has been found to be a non-competitive direct inhibitor of brain microsomal long-chain fatty acyl-CoA synthetase. Inhibition of this enzyme decreases available arichidonyl-CoA, a substrate in the production of inflammatory prostaglandins. It is thought that this may be a mechanism behind valproate's efficacy in migraine prophylaxis as migraines are routinely treated with non-steroidal anti-inflammatory drugs which also inhibit prostaglandin production. Finally, valproate acts as a direct histone deactylase (HDAC) inhibitor. Hyperacetylation of lysine residues on histones promoted DNA relaxation and allows for increased gene transcription. The scope of valproate's genomic effects is wide with 461 genes being up or down-regulated. The relation of these genomic effects to therapeutic value is not fully characterized however H3 and H4 hyperacetylation correlates with improvement of symptoms in bipolar patients. Histone hyperacetylation at the BDNF gene, increasing BDNF expression, post-seizure is known to occur and is thought to be a neuroprotective mechanism which valproate may strengthen or prolong. H3 hyperacetylation is associated with a reduction in glyceraldehyde-3-phosphate dehydrogenase, a pro-apoptotic enzyme, contributing further to valproate's neuroprotective 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 intravenous and oral forms of valproic acid are expected to produce the same AUC, Cmax, and Cmin at steady-state. The oral delayed-release tablet formulation has a Tmax of 4 hours. Differences in absorption rate are expected from other formulations but are not considered to be clinically important in the context of chronic therapy beyond impacting frequency of dosing. Differences in absorption may create earlier Tmax or higher Cmax values on initiation of therapy and may be affected differently by meals. The extended release tablet formulation had Tmax increase from 4 hours to 8 hours when taken with food. In comparison, the sprinkle capsule formulation had Tmax increase from 3.3 hours to 4.8 hours. Bioavailability is reported to be approximately 90% with all oral formulations with enteric-coated forms possibly reaching 100%. •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): 11 L/1.73m. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding is linear at low concentrations with a free fraction of approximately 10% at 40 mcg/mL but becomes non-linear at higher concentrations with a free fraction of 18.5% at 135 mcg/mL. This may be due to binding at separate high and low-affinity sites on albumin proteins. Binding is expected to decrease in the elderly and patients with hepatic dysfunction. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Most drug is metabolized to glucuronide conjugates (30-50%) of the parent drug or of metabolites. Another large portion is metabolized through mitochondrial β-oxidation (40%). The remainder of metabolism (15-20%) occurs through oxidation, hydroxylation, and dehydrogenation at the ω, ω 1, and ω 2 positions resulting in the formation of hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Most drug is eliminated through hepatic metabolism, about 30-50%. The other major contributing pathway is mitochondrial β-oxidation, about 40%. Other oxidative pathways make up an additional 15-20%. Less than 3% 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): 13-19 hours. The half-life in neonates ranges from 10-67 hours while the half-life in pediatric patients under 2 months of age ranges from 7-13 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): 0.56 L/hr/m Pediatric patients between 3 months and 10 years of age have 50% higher clearances by weight. Pediatric patients 10 years of age or older approximate adult values. •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 Values Oral, mouse: 1098 mg/kg Oral, rat: 670 mg/kg Overdose Symptoms of overdose include somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported, however patients have recovered from valproate serum concentrations as high as 2120 mcg/mL. The unbound fraction may be removed by hemodialysis. Naloxone has been demonstrated to reverse the CNS depressant effects of overdose but may also reverse the anti-epileptic effects. Reproductive Toxicity Valproate use in pregnancy is known to increase the risk of neural tube defects and other structural abnormalities. The risk of spina bifida increases from 0.06-0.07% in the normal population to 1-2% in valproate users. The North American Antiepileptic Drug (NAAED) Pregnancy Registry reports a major malformation rate of 9-11%, 5 times the baseline rate. These malformations include neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems. Other antiepileptic drugs, lamotrigine, carbemazepine, and phenytoin, have been found to reduce IQ in children exposed in utero. Valproate was also studied however the results did not achieve statistical significance (97 IQ (CI: 94-101)). Observational studies report an absolute risk increase of 2.9% (relative risk 2.9 times baseline) of autism spectrum disorder in children exposed to valproate in utero. There have been case reports of fatal hepatic failure in children of mothers who used valproate during pregnancy. There have been reports of male infertility when taking valproate. Lactation Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk. Other Toxicity Considerations Use in pediatrics under 2 years of age increases the risk of fatal hepatotoxicity. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Depakene, Depakote, Epival •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): acide valproïque ácido valproico acidum valproicum Dipropylacetic acid Valproate Valproic acid Valproinsäure •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): Valproic acid is an anticonvulsant used to control complex partial seizures and both simple and complex absence seizures. 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 Valsartan interact?

•Drug A: Adalimumab •Drug B: Valsartan •Severity: MODERATE •Description: The metabolism of Valsartan 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): Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. It is also used in combination with sacubitril. •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): Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. Hyperkalemia Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required. •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): Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril ) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 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): After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive 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): The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Valsartan is highly bound to serum proteins (95%), mainly serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose 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): After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 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): Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total 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): Approximate LD50 >2000 mg/kg (Gavage, rat) Reproductive Toxicology Studies No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation. Pregnancy When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dafiro, Diovan, Diovan Hct, Entresto, Exforge, Exforge Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Valsartan •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): Valsartan is an angiotensin-receptor blocker used to manage hypertension alone or in combination with other antihypertensive agents and to manage heart failure in patients who are intolerant to ACE inhibitors.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Valsartan interact? Information: •Drug A: Adalimumab •Drug B: Valsartan •Severity: MODERATE •Description: The metabolism of Valsartan 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): Valsartan is indicated for the treatment of hypertension to reduce the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. It is also indicated for the treatment of heart failure (NYHA class II-IV) and for left ventricular dysfunction or failure after myocardial infarction when the use of an angiotensin-converting enzyme inhibitor (ACEI) is not appropriate. It is also used in combination with sacubitril. •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): Valsartan inhibits the pressor effects of angiotensin II with oral doses of 80 mg inhibiting the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. Hypotension Excessive hypotension was rarely seen (0.1%) in patients with uncomplicated hypertension treated with valsartan alone. In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients receiving high doses of diuretics, symptomatic hypotension may occur. This condition should be corrected prior to administration of valsartan, or the treatment should start under close medical supervision. Caution should be observed when initiating therapy in patients with heart failure. Patients with heart failure given valsartan commonly have some reduction in blood pressure, but discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed. In controlled trials in heart failure patients, the incidence of hypotension in valsartan-treated patients was 5.5% compared to 1.8% in placebo-treated patients. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. Impaired Renal Function Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan. Hyperkalemia Some patients with heart failure have developed increases in potassium. These effects are usually minor and transient, and they are more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of valsartan may be required. •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): Valsartan belongs to the angiotensin II receptor blocker (ARB) family of drugs, which selectively bind to angiotensin receptor 1 (AT1) and prevent angiotensin II from binding and exerting its hypertensive effects. These include vasoconstriction, stimulation and synthesis of aldosterone and ADH, cardiac stimulation, and renal reabsorption of sodium among others. Overall, valsartan's physiologic effects lead to reduced blood pressure, lower aldosterone levels, reduced cardiac activity, and increased excretion of sodium. Valsartan also affects the renin-angiotensin aldosterone system (RAAS), which plays an important role in hemostasis and regulation of kidney, vascular, and cardiac functions. Pharmacological blockade of RAAS via AT1 receptor blockade inhibits negative regulatory feedback within RAAS which is a contributing factor to the pathogenesis and progression of cardiovascular disease, heart failure, and renal disease. In particular, heart failure is associated with chronic activation of RAAS, leading to inappropriate fluid retention, vasoconstriction, and ultimately a further decline in left ventricular function. ARBs have been shown to have a protective effect on the heart by improving cardiac function, reducing afterload, increasing cardiac output and prevent ventricular hypertrophy. The angiotensin-converting enzyme inhibitor (ACEI) class of medications (which includes drugs such as ramipril, lisinopril, and perindopril ) inhibits the conversion of angiotensin I to angiotensin II by inhibiting the ACE enzyme but does not prevent the formation of all angiotensin II. ARB activity is unique in that it blocks all angiotensin II activity, regardless of where or how it was synthesized. Valsartan is commonly used for the management of hypertension, heart failure, and type 2 diabetes-associated nephropathy, particularly in patients who are unable to tolerate ACE inhibitors. ARBs such as valsartan have been shown in a number of large-scale clinical outcomes trials to improve cardiovascular outcomes including reducing risk of myocardial infarction, stroke, the progression of heart failure, and hospitalization. Valsartan also slows the progression of diabetic nephropathy due to its renoprotective effects. Improvements in chronic kidney disease with valsartan include both clinically and statistically significant decreases in urinary albumin and protein excretion in patients diagnosed with type 2 diabetes and in nondiabetic patients diagnosed with chronic kidney disease. Valsartan also binds to the AT2 receptor, however AT2 is not known to be associated with cardiovascular homeostasis like AT1. Valsartan has about 20,000-fold higher affinity for the AT1 receptor than for the AT2 receptor. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 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): After one oral dose, the antihypertensive activity of valsartan begins within approximately 2 hours and peaks within 4-6 hours in most patients. Food decreases the exposure to orally administered valsartan by approximately 40% and peak plasma concentration by approximately 50%. AUC and Cmax values of valsartan generally increase linearly with increasing dose over the therapeutic dose range. Valsartan does not accumulate appreciably in plasma following repetitive 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): The steady-state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Valsartan is highly bound to serum proteins (95%), mainly serum albumin. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Valsartan undergoes minimal liver metabolism and is not biotransformed to a high degree, as only approximately 20% of a single dose is recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. In vitro metabolism studies involving recombinant CYP 450 enzymes indicated that the CYP 2C9 isoenzyme is responsible for the formation of valeryl-4-hydroxy valsartan. Valsartan does not inhibit CYP 450 isozymes at clinically relevant concentrations. CYP 450 mediated drug interaction between valsartan and coadministered drugs are unlikely because of the low extent of metabolism. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose 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): After intravenous (IV) administration, valsartan demonstrates bi-exponential decay kinetics, with an average elimination half-life of about 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): Following intravenous administration, plasma clearance of valsartan is approximately 2 L/hour and its renal clearance is 0.62 L/hour (about 30% of total 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): Approximate LD50 >2000 mg/kg (Gavage, rat) Reproductive Toxicology Studies No teratogenic effects were seen when valsartan was given to pregnant mice and rats at oral doses up to 600 mg/kg/day and to pregnant rabbits at oral doses reaching up to 10 mg/kg/day. Despite this, marked decreases in fetal weight, pup birth weight, pup survival rate, and delays in developmental milestones were noted in studies in which parental rats were treated with valsartan at oral, maternally toxic doses of 600 mg/kg/day during the organogenesis period or during late gestation and lactation. Pregnancy When used in pregnancy, drugs that act directly on the renin-angiotensin system (RAAS) can cause injury and death to the developing fetus. When pregnancy is detected, valsartan should be discontinued as soon as possible. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Dafiro, Diovan, Diovan Hct, Entresto, Exforge, Exforge Hct •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Valsartan •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): Valsartan is an angiotensin-receptor blocker used to manage hypertension alone or in combination with other antihypertensive agents and to manage heart failure in patients who are intolerant to ACE inhibitors. 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 Vandetanib interact?

•Drug A: Adalimumab •Drug B: Vandetanib •Severity: MAJOR •Description: The metabolism of Vandetanib 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): Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Because Vandetanib can prolong the Q-T interval, it is contraindicated for use in patients with serious cardiac complications such as congenital long QT syndrome and uncompensated heart failure. •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): Mean IC50 of approximately 2.1 μg/mL. •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): ZD-6474 is a potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases. VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU. •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): Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months. •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 of about 7450 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of about 90%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% 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): Median half life of 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): 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): Caprelsa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vandetanib •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): Vandetanib is an antineoplastic kinase inhibitor used to treat symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Question: Does Adalimumab and Vandetanib interact? Information: •Drug A: Adalimumab •Drug B: Vandetanib •Severity: MAJOR •Description: The metabolism of Vandetanib 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): Vandetanib is currently approved as an alternative to local therapies for both unresectable and disseminated disease. Because Vandetanib can prolong the Q-T interval, it is contraindicated for use in patients with serious cardiac complications such as congenital long QT syndrome and uncompensated heart failure. •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): Mean IC50 of approximately 2.1 μg/mL. •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): ZD-6474 is a potent and selective inhibitor of VEGFR (vascular endothelial growth factor receptor), EGFR (epidermal growth factor receptor) and RET (REarranged during Transfection) tyrosine kinases. VEGFR- and EGFR-dependent signalling are both clinically validated pathways in cancer, including non-small-cell lung cancer (NSCLC). RET activity is important in some types of thyroid cancer, and early data with vandetanib in medullary thyroid cancer has led to orphan-drug designation by the regulatory authorities in the USA and EU. •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): Slow- peak plasma concentrations reached at a median 6 hours. On multiple dosing, Vandetanib accumulates about 8 fold with steady state reached after around 3 months. •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 of about 7450 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Protein binding of about 90%. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Unchanged vandentanib and metabolites vandetanib N-oxide and N-desmethyl vandetanib were detected in plasma, urine and feces. N-desmethyl-vandetanib is primarily produced by CYP3A4, and vandetanib-N-oxide is primarily produced by flavin–containing monooxygenase enzymes FMO1 and FMO3. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): About 69% was recovered following 21 days after a single dose of vandentanib. 44% was found in feces and 25% 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): Median half life of 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): 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): Caprelsa •Synonyms (Drug A): No synonyms listed •Synonyms (Drug B): Vandetanib •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): Vandetanib is an antineoplastic kinase inhibitor used to treat symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic 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 CYP3A4 substrates with a narrow therapeutic index. The severity of the interaction is major.

Does Adalimumab and Vardenafil interact?

•Drug A: Adalimumab •Drug B: Vardenafil •Severity: MODERATE •Description: The metabolism of Vardenafil 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): Vardenafil is indicated for the treatment of erectile dysfunction. •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): Vardenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), an enzyme responsible for the degradation of cGMP in the corpus cavernosum. The presence of cGMP in the corpus cavernosum leads to smooth muscle relaxation, an increased inflow of blood and an erection. Therefore, in patients with erectile dysfunction given vardenafil, normal sexual stimulation will increase cGMP levels in the corpus cavernosum. Without sexual stimulation and no cGMP production, vardenafil should not cause an erection. Vardenafil should not be used in men for whom sexual activity is not recommended due to their underlying cardiovascular status. There is also a risk of developing prolonged erections that last longer than 4 hours, as well as priapism. In the event of a sudden loss of vision in one or both eyes, patients should stop using vardenafil. Patients taking PDE5 inhibitors, such as vardenafil, may also develop sudden hearing loss and experience a prolonged QT 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): Vardenafil inhibits cyclic guanosine monophosphate (GMP) specific phosphodiesterase type 5 (PDE5), which is responsible for the degradation of cyclic GMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The tissue concentration of cyclic GMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs), and the most abundant PDE in the human corpus cavernosum is PDE5. Therefore, the inhibition of PDE5 by vardenafil enhances erectile function by increasing the amount of cyclic GMP. •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): Over the recommended dose range, vardenafil has a dose-proportional pharmacokinetics profile. In healthy male volunteers given a single oral dose of 20 mg of vardenafil, maximum plasma concentrations were reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state, and 0.00018% of the dose was detected in semen 1.5 hours after dosing. Vardenafil has a bioavailability of approximately 15%. High-fat meals cause a C max reduction of 18%-50%; however, no changes were detected in AUC or T max. •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): Vardenafil has a steady-state volume of distribution of 208 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 95% of vardenafil and its major circulating metabolite is bound to plasma proteins. Their protein binding is reversible and independent of total drug concentrations. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Vardenafil is mainly metabolized by CYP3A4 in the liver, although CYP3A5 and CYP2C isoforms also contribute to its metabolism. The major circulating metabolite, M1 (N-desethylvardenafil), results from desethylation at the piperazine moiety of vardenafil, and has a plasma concentration of approximately 26% of that of the parent compound. M1 has a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Vardenafil is excreted as metabolites mainly through feces and urine. Approximately 91-95% of administered oral dose is found in feces, while 2-6% of administered oral dose is found 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): Vardenafil and its primary metabolite (M1) have a terminal half-life of 4-5 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): Vardenafil has a total body clearance of 56 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): Healthy male volunteers given a single dose of 120 mg of vardenafil experienced reversible back pain, myalgia and abnormal vision. Patients given vardenafil once daily over 4 weeks in single doses up to 80 mg and multiple doses up to 40 mg did not present serious adverse side effects. Cases of severe back pain were observed when 40 mg of vardenafil was administered twice daily; however patients did not present muscle or neurological toxicity. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine. No carcinogenic effects were detected in rats and mice given vardenafil daily for 24 months. Vardenafil was not mutagenic or clastogenic, and did not have an effect in fertility in male and female rats given up to 100 mg/kg/day for 28 days prior to mating in males, and for 14 days prior to mating and through day 7 of gestation in females. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Levitra, Staxyn •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): Vardenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction.

The formation of CYP450 enzymes is inhibited by the presence of increased levels of cytokines during chronic inflammation. 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 Vardenafil interact? Information: •Drug A: Adalimumab •Drug B: Vardenafil •Severity: MODERATE •Description: The metabolism of Vardenafil 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): Vardenafil is indicated for the treatment of erectile dysfunction. •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): Vardenafil is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), an enzyme responsible for the degradation of cGMP in the corpus cavernosum. The presence of cGMP in the corpus cavernosum leads to smooth muscle relaxation, an increased inflow of blood and an erection. Therefore, in patients with erectile dysfunction given vardenafil, normal sexual stimulation will increase cGMP levels in the corpus cavernosum. Without sexual stimulation and no cGMP production, vardenafil should not cause an erection. Vardenafil should not be used in men for whom sexual activity is not recommended due to their underlying cardiovascular status. There is also a risk of developing prolonged erections that last longer than 4 hours, as well as priapism. In the event of a sudden loss of vision in one or both eyes, patients should stop using vardenafil. Patients taking PDE5 inhibitors, such as vardenafil, may also develop sudden hearing loss and experience a prolonged QT 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): Vardenafil inhibits cyclic guanosine monophosphate (GMP) specific phosphodiesterase type 5 (PDE5), which is responsible for the degradation of cyclic GMP in the corpus cavernosum located around the penis. Penile erection during sexual stimulation is caused by increased penile blood flow resulting from the relaxation of penile arteries and corpus cavernosal smooth muscle. This response is mediated by the release of nitric oxide (NO) from nerve terminals and endothelial cells, which stimulates the synthesis of cyclic GMP in smooth muscle cells. Cyclic GMP causes smooth muscle relaxation and increased blood flow into the corpus cavernosum. The tissue concentration of cyclic GMP is regulated by both the rates of synthesis and degradation via phosphodiesterases (PDEs), and the most abundant PDE in the human corpus cavernosum is PDE5. Therefore, the inhibition of PDE5 by vardenafil enhances erectile function by increasing the amount of cyclic GMP. •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): Over the recommended dose range, vardenafil has a dose-proportional pharmacokinetics profile. In healthy male volunteers given a single oral dose of 20 mg of vardenafil, maximum plasma concentrations were reached between 30 minutes and 2 hours (median 60 minutes) after oral dosing in the fasted state, and 0.00018% of the dose was detected in semen 1.5 hours after dosing. Vardenafil has a bioavailability of approximately 15%. High-fat meals cause a C max reduction of 18%-50%; however, no changes were detected in AUC or T max. •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): Vardenafil has a steady-state volume of distribution of 208 L. •Protein binding (Drug A): No protein binding available •Protein binding (Drug B): Approximately 95% of vardenafil and its major circulating metabolite is bound to plasma proteins. Their protein binding is reversible and independent of total drug concentrations. •Metabolism (Drug A): No metabolism available •Metabolism (Drug B): Vardenafil is mainly metabolized by CYP3A4 in the liver, although CYP3A5 and CYP2C isoforms also contribute to its metabolism. The major circulating metabolite, M1 (N-desethylvardenafil), results from desethylation at the piperazine moiety of vardenafil, and has a plasma concentration of approximately 26% of that of the parent compound. M1 has a phosphodiesterase selectivity profile similar to that of vardenafil and an in vitro inhibitory potency for PDE5 28% of that of vardenafil. •Route of elimination (Drug A): Adalimumab is most likely removed by opsonization via the reticuloendothelial system. •Route of elimination (Drug B): Vardenafil is excreted as metabolites mainly through feces and urine. Approximately 91-95% of administered oral dose is found in feces, while 2-6% of administered oral dose is found 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): Vardenafil and its primary metabolite (M1) have a terminal half-life of 4-5 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): Vardenafil has a total body clearance of 56 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): Healthy male volunteers given a single dose of 120 mg of vardenafil experienced reversible back pain, myalgia and abnormal vision. Patients given vardenafil once daily over 4 weeks in single doses up to 80 mg and multiple doses up to 40 mg did not present serious adverse side effects. Cases of severe back pain were observed when 40 mg of vardenafil was administered twice daily; however patients did not present muscle or neurological toxicity. In cases of overdose, standard supportive measures should be taken as required. Renal dialysis is not expected to accelerate clearance as vardenafil is highly bound to plasma proteins and not significantly eliminated in the urine. No carcinogenic effects were detected in rats and mice given vardenafil daily for 24 months. Vardenafil was not mutagenic or clastogenic, and did not have an effect in fertility in male and female rats given up to 100 mg/kg/day for 28 days prior to mating in males, and for 14 days prior to mating and through day 7 of gestation in females. •Brand Names (Drug A): Amjevita, Cyltezo, Humira, Hyrimoz, Yusimry •Brand Names (Drug B): Levitra, Staxyn •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): Vardenafil is a phosphodiesterase 5 inhibitor used to treat erectile dysfunction. 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.