Bexarotene (Systemic)
Brand name: Targretin
Drug class: Antineoplastic Agents
VA class: AN900
Chemical name: 4-[1-(5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)ethenyl]benzoic acid
Molecular formula: C24H28O2
CAS number: 153559-49-0
Warning
May cause birth defects in humans; teratogenicity and embryolethality demonstrated in animals. Contraindicated in pregnant women. See Fetal/Neonatal Morbidity and Mortality under Cautions.
Introduction
Antineoplastic agent; synthetic retinoid analog.
Uses for Bexarotene (Systemic)
Cutaneous T-cell Lymphoma
Treatment of skin manifestations of cutaneous T-cell lymphoma (CTCL) in patients who are refractory to at least one prior systemic therapy.
Bexarotene (Systemic) Dosage and Administration
Administration
Oral Administration
Administer orally once daily with a meal.
Dosage
Adults
CTCL
Oral
Initially, 300 mg/m2 daily.
If intolerable adverse effects occur, decrease dosage to 200 mg/m2 daily, then 100 mg/m2 daily, or temporarily discontinue. When toxicity is controlled, carefully readjust dosage upward.
If no tumor response is observed after 8 weeks and the 300-mg/m2 daily dosage is well tolerated, increase to 400 mg/m2 daily with careful monitoring.
Continue as long as benefit is derived from therapy. Optimum duration is not known.
Cautions for Bexarotene (Systemic)
Contraindications
-
Known or suspected pregnancy.
-
Known hypersensitivity to bexarotene or any ingredient in the formulation.
Warnings/Precautions
Warnings
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity and embryolethality demonstrated in animals.
Exclude pregnancy 1 week prior to initiation of therapy. Initiate therapy on second or third day of normal menstrual period. Repeat pregnancy tests monthly during therapy. To facilitate pregnancy test assessment and counseling, dispense no more than 1 month supply.
Use contraception (2 reliable forms, including at least 1 nonhormonal method) for 1 month before, during, and for 1 month after administration. Male patients should use condoms during sexual intercourse with women who are or may become pregnant.
If pregnancy occurs, immediately discontinue and apprise of potential fetal hazard.
Effects on Lipoproteins
Lipid abnormalities (e.g., hyperlipidemia, elevated fasting triglycerides and cholesterol, decreased HDL-cholesterol) occur in most patients; usually develop within 2–4 weeks and are reversible with cessation of therapy.
If fasting triglycerides are or become elevated, institute antilipemic therapy and reduce bexarotene dosage or suspend therapy. Gemfibrozil is not recommended. (See Specific Drugs and Foods under Interactions.) Monitor fasting blood lipid levels weekly until lipid response is established, then at 8 week intervals.
Pancreatitis
Possible acute pancreatitis; possibly fatal. Patients with risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia or diabetes mellitus, excessive alcohol consumption, biliary tract disease, or therapy with drugs associated with pancreatic toxicity or known to increase triglyceride concentrations) generally should not receive bexarotene.
Hepatic Effects
Possible elevations in AST and ALT; usually resolve within 1 month following decrease in dosage or discontinuance.
Monitor liver function tests at baseline; after 1, 2, and 4 weeks of treatment; and at least every 8 weeks thereafter. Consider discontinuance if transaminases or bilirubin increase to 3 times ULN.
Thyroid Effects
Possible hypothyroidism. Consider thyroid supplementation in patients with laboratory evidence of hypothyroidism. Monitoring of thyroid function tests recommended.
Hematologic Effects
Leukopenia (generally neutropenia) possible, rarely associated with serious adverse events; time to onset usually 4–8 weeks, with resolution occurring within 30 days of dosage reduction or discontinuance of the drug in most patients. Obtain WBC with differential at baseline and periodically during therapy.
Ocular Effects
New cataracts or worsening of existing cataracts possible. Ophthalmologic evaluation recommended if visual difficulties occur.
Sensitivity Reactions
Hypersensitivity
Use with caution in patients with known hypersensitivity to retinoids.
Photosensitivity Reactions
Sunburn and skin sensitivity to sunlight possible in patients exposed to direct sunlight. Minimize exposure to sunlight and artificial UV light.
Specific Populations
Pregnancy
Category X. (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)
Lactation
Not known whether bexarotene is distributed into milk. Discontinue nursing or the drug.
Pediatric Use
Safety and efficacy not established in children <18 years of age.
Geriatric Use
No substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.
Hepatic Impairment
Use only with great caution. (See Hepatic Effects under Cautions and also Elimination: Special Populations under Pharmacokinetics.)
Common Adverse Effects
Lipid abnormalities, hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, dry skin.
Interactions for Bexarotene (Systemic)
Metabolized by CYP3A4. Possibly also an inducer of CYP3A4.
Drugs Affecting Hepatic Microsomal Enzymes
Inhibitors or inducers of CYP3A4: potential pharmacokinetic interaction (altered bexarotene metabolism).
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP3A4: potential pharmacokinetic interaction (decreased plasma substrate concentrations).
Protein-bound Drugs
Potential pharmacokinetic interaction (bexarotene displacement by, or bexarotene displacement of, other protein-bound drugs).
Specific Drugs and Foods
Drug or Food |
Interaction |
Comments |
---|---|---|
Antidiabetic agents (e.g., insulin, sulfonylureas, other oral antidiabetic agents) |
Potential increased incidence of hypoglycemia |
Use concomitantly with caution |
Antifungals (e.g., itraconazole, ketoconazole) |
Possible increased plasma bexarotene concentrations |
|
Atorvastatin |
Pharmacokinetic interaction unlikely |
|
Erythromycin |
Possible increased plasma bexarotene concentrations |
|
Gemfibrozil |
Increased plasma bexarotene concentrations |
Concomitant use not recommended |
Grapefruit juice |
Possible increased plasma bexarotene concentrations |
|
Hormonal contraceptives |
Decreased plasma concentrations of hormonal contraceptives |
|
Phenobarbital |
Possible decreased plasma bexarotene concentrations |
|
Phenytoin |
Possible decreased plasma bexarotene concentrations |
|
Rifampin |
Possible decreased plasma bexarotene concentrations |
|
Tamoxifen |
Decreased plasma tamoxifen concentrations |
|
Vitamin A |
Possible increased toxicity |
Bexarotene (Systemic) Pharmacokinetics
Absorption
Bioavailability
Absorbed following oral administration, with peak plasma concentrations attained within approximately 2 hours.
Food
Peak plasma concentrations and AUC (after 75–300 mg doses) increased by approximately 48 and 35%, respectively, after a meal containing fat compared with glucose solution.
Distribution
Extent
Distribution into body tissues and fluids has not been evaluated.
It is not known whether bexarotene is distributed into milk.
Plasma Protein Binding
>99%.
Special Populations
In patients with renal impairment, possible altered protein binding and pharmacokinetics.
Elimination
Metabolism
Metabolized extensively in the liver; in vitro, metabolized principally via CYP3A4 oxidation. Oxidative metabolites active in vitro; relative contributions of parent drug or metabolites to safety and efficacy unknown.
Elimination Route
Bexarotene and its metabolites eliminated principally via biliary excretion; not excreted in urine in appreciable amounts.
Half-life
Approximately 7 hours.
Special Populations
In patients with hepatic impairment, greatly decreased clearance expected.
Stability
Storage
Oral
Capsules
2–25°C. Avoid exposure to high temperatures and humidity after bottle is opened; protect from light.
Actions
-
Selectively binds with and activates retinoid X receptor (RXR) subtypes (RXRα, RXRβ, and RXRγ). Activated RXRs function as transcription factors that regulate the expression of genes controlling cellular differentiation and proliferation.
-
Exact mechanism(s) of action not determined, but bexarotene is active in all clinical stages of CTCL.
Advice to Patients
-
Importance of women informing clinicians immediately if they are or plan to become pregnant or plan to breast-feed.
-
Importance of women and men taking measures to avoid pregnancy because of risk to fetus.
-
Importance of men using condoms during sexual intercourse while receiving the drug and for at least 1 month after discontinuing the drug.
-
Importance of monthly pregnancy tests.
-
Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
-
Importance of taking bexarotene with, or immediately following, a meal.
-
Risk of photosensitivity reactions.
-
Risk of hypoglycemia in patients being treated for diabetes mellitus.
-
Importance of adhering to laboratory appointment schedules.
-
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
75 mg |
Targretin (with povidone) |
Ligand |
AHFS DI Essentials™. © Copyright 2023, Selected Revisions May 1, 2006. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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