Bexarotene (Systemic)
Brand names: Targretin
Drug class:
Antineoplastic Agents
Usage of 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.
Within CTCL, some experts recommend oral bexarotene with skin directed therapies in mycosis fungoides uncontrolled with initial treatment, or with extracorporeal photopheresis in Sézary syndrome as first-line therapy.
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How to use Bexarotene (Systemic)
General
Pretreatment Screening
Patient Monitoring
Administration
Oral Administration
Administer orally once daily with a meal.
Dosage
Adults
CTCL OralInitially, 300 mg/m2 daily.
Refer to Table 1 for the initial bexarotene dose of 300 mg/m2 daily according to BSA.
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.
Table 1. Bexarotene Dose Based on an Initial Dose of 300mg/m2 Daily According to BSA1Body Surface Area (m2)
Total Daily Dose (mg/day)
0.88–1.12
300
1.13–1.37
375
1.38–1.62
450
1.63–1.87
525
1.88–2.12
600
2.13–2.37
675
2.38–2.62
750
Dosage Modification for ToxicityIf 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.
Special Populations
Hepatic Impairment
No specific dosage recommendations for hepatic impairment.
Renal Impairment
No specific dosage recommendations for renal impairment.
Geriatric Patients
No specific dosage recommendations for geriatric patients.
Warnings
Contraindications
Warnings/Precautions
Fetal/Neonatal Morbidity and Mortality
A boxed warning about the risk of birth defects is included in the prescribing information for bexarotene. 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.
If pregnancy occurs, immediately discontinue and apprise of potential fetal hazard.
Hyperlipidemia
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 due to a potential drug-drug interaction. Monitor fasting blood lipid levels weekly until lipid response is established, then at 8-week intervals. For patients without hyperlipidemia, monitoring can be performed less frequently after 2–4 weeks of therapy.
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. Interrupt bexarotene treatment and evaluate if pancreatitis is suspected.
Hepatotoxicity, Cholestasis, and Hepatic Failure
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 interruption or discontinuance if transaminases or bilirubin increase to 3 times ULN.
Hypothyroidism
Possible hypothyroidism. Consider thyroid supplementation in patients with laboratory evidence of hypothyroidism. Obtain baseline thyroid function tests and monitor during treatment.
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 CBC with differential at baseline and periodically during therapy.
Cataracts
New cataracts or worsening of existing cataracts possible. Ophthalmologic evaluation recommended if visual difficulties occur.
Vitamin A Supplementation Hazard
Due to the relationship between bexarotene and vitamin A, limit vitamin A intake to <15,000 IU/day to limit toxic effects.
Photosensitivity Reactions
Sunburn and skin sensitivity to sunlight possible in patients exposed to direct sunlight. Minimize exposure to sunlight and artificial UV light.
Hypoglycemia Risk in Patients with Diabetes Mellitus
Patients using insulin, sulfonylureas, thiazolidinediones, or other oral agents while on bexarotene are at an increased risk for hypoglycemia, since bexarotene may enhance their effects. When used as monotherapy, bexarotene has not been associated with hypoglycemia.
Drug-Laboratory Test Interaction
In patients with ovarian cancer, CA125 assay values may be increased by bexarotene.
Specific Populations
PregnancyContraindicated in pregnancy. Associated with birth defects in humans. In animal studies, bexarotene administration resulted in fetal harm. Obtain a negative serum pregnancy test within 1 week prior to starting bexarotene therapy, and perform pregnancy testing at monthly intervals during bexarotene therapy. (See Fetal/Neonatal Morbidity and Mortality and also Contraindications under Cautions.)
LactationNot known whether bexarotene is distributed into milk. Discontinue nursing or the drug.
Pediatric UseSafety and efficacy not established in children <18 years of age.
Females and Males of Reproductive PotentialObtain a negative serum pregnancy test within 1 week prior to starting bexarotene therapy, and perform pregnancy testing at monthly intervals during bexarotene therapy. Use contraception (with 2 reliable forms, including at least one nonhormonal method) for 1 month before, during, and for at least 1 month after bexarotene administration. Male patients receiving the drug should use condoms during sexual intercourse with women who are or may become pregnant, and for at least 1 month after discontinuing bexarotene.
Geriatric UseNo substantial differences in safety relative to younger adults, but increased sensitivity cannot be ruled out.
Hepatic ImpairmentNo formal studies have been conducted with bexarotene. Hepatic impairment may reduce drug clearance; monitor for signs and symptoms of toxicity with reduced hepatic function.
Renal ImpairmentNo formal studies have been conducted with bexarotene. Due to changes in protein binding, the pharmacokinetics of bexarotene may be altered in renal impairment.
Common Adverse Effects
The most common adverse reactions (occurring in >10% of patients in clinical trials and at least possibly related to treatment) include: lipid abnormalities (elevated triglycerides, elevated total and LDL cholesterol, and decreased HDL cholesterol), hypothyroidism, headache, asthenia, rash, leukopenia, anemia, nausea, infection, peripheral edema, abdominal pain, dry skin.
What other drugs will affect Bexarotene (Systemic)
Metabolized by CYP3A4. Possibly also an inducer of CYP3A4.
In vitro, bexarotene inhibits CYP2C8 and induces CYP3A4.
In vitro, bexarotene does not significantly inhibit CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.
Drugs Affected 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)
Likely no interaction that alters bexarotene plasma concentrations
Atorvastatin
Decreased atorvastatin plasma concentrations
Gemfibrozil
Increased plasma bexarotene concentrations
Concomitant use not recommended
Hormonal contraceptives
Decreased plasma concentrations of hormonal contraceptives
Paclitaxel (plus Carboplatin)
Increased plasma bexarotene concentrations ; when administered with carboplatin
Decreased plasma concentrations of paclitaxel
Tamoxifen
Decreased plasma tamoxifen concentrations
Vitamin A
Possible increased toxicity
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