BEXAROTENE Drug Interactions: What You Need to Know

INTERACTIONS Effect of Other Drugs on Bexarotene Capsules Gemfibrozil: Concomitant administration of bexarotene capsules and gemfibrozil resulted in increases in plasma concentrations of bexarotene. Concomitant administration of gemfibrozil with bexarotene capsules is not recommended. Effect of Bexarotene Capsules on Other Drugs Bexarotene may be an inducer for the CYP3A4 enzymes, and may reduce plasma concentrations of other substrates metabolized by CYP3A4. Drug products which may be affected include oral or other systemic hormonal contraceptives. Thus, if treatment with bexarotene capsules is intended for a female with reproductive potential, it is strongly recommended that a non-hormonal contraception be considered [ see Use in Specific Populations (8.3) , Clinical Pharmacology (12.3) ].

Laboratory Test

Interference CA125 assay values in patients with ovarian cancer may be increased by bexarotene capsule therapy.

Drug Interactions

Effect of Other Drugs on Bexarotene CYP3A4 Inhibitors/Inducers: In a clinical study, concomitant administration of multiple doses of ketoconazole with bexarotene capsules did not alter bexarotene plasma concentrations. This suggests that bexarotene elimination is not dependent on CYP3A4 metabolism. Paclitaxel plus Carboplatin: The co-administration of paclitaxel (200 mg/m 2 IV dose over 3 hours) plus carboplatin (at a dose expected to achieve an AUC of 6 mg●min/mL) with bexarotene capsules (400 mg/m 2 orally once daily) increased the exposure to bexarotene (AUC 0-24 and C max ) by 2-fold compared to bexarotene capsules alone. Atorvastatin: Bexarotene concentrations were not affected by concomitant atorvastatin administration. Effect of Bexarotene on Other Drugs Bexarotene did not significantly inhibit the following enzymes in human liver microsomes: CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. In vitro data suggested a potential for bexarotene to inhibit CYP2C8 and induce CYP3A4. Atorvastatin: The exposure (AUC) to atorvastatin (a substrate for CYP3A4) decreased by half when atorvastatin was co-administered with bexarotene capsules (400 mg/m 2 orally once daily). Tamoxifen: Based on interim data, concomitant administration of bexarotene capsules and tamoxifen resulted in approximately a 35% decrease in plasma concentrations of tamoxifen, possibly through induction of CYP3A4 by bexarotene. Paclitaxel: The exposure (AUC) to paclitaxel (a substrate for CYP3A4 and CYP2C8) decreased by 19% when paclitaxel (200 mg/m 2 IV dose over 3 hours) was co-administered with bexarotene capsules (400 mg/m 2 orally once daily). Carboplatin: The co-administration of bexarotene capsules (400 mg/m 2 orally once daily) had no effect on the exposure to free or total carboplatin.

CONTRAINDICATIONS Bexarotene gel, 1% is contraindicated in patients with a known hypersensitivity to bexarotene or other components of the product.

Pregnancy

Bexarotene gel, 1% may cause fetal harm when administered to a pregnant woman. Bexarotene gel must not be given to a pregnant woman or a woman who intends to become pregnant. If a woman becomes pregnant while taking bexarotene gel, bexarotene gel must be stopped immediately and the woman given appropriate counseling. Bexarotene caused malformations when administered orally to pregnant rats during days 7 to 17 of gestation. Developmental abnormalities included incomplete ossification at 4 mg/kg/day and cleft palate, depressed eye bulge/microphthalmia, and small ears at 16 mg/kg/day. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality. The no-effect oral dose in rats was 1 mg/kg/day. Plasma bexarotene concentrations in patients with CTCL applying bexarotene gel, 1% were generally less than one hundredth the C max associated with dysmorphogenesis in rats, although some patients had C max levels that were approximately one eighth the concentration associated with dysmorphogenesis in rats. Women of child-bearing potential should be advised to avoid becoming pregnant when bexarotene gel is used. The possibility that a woman of child-bearing potential is pregnant at the time therapy is instituted should be considered. A negative pregnancy test (e.g., serum beta-human chorionic gonadotropin, beta-HCG) with a sensitivity of at least 50 mIU/L should be obtained within one week prior to bexarotene gel therapy, and the pregnancy test must be repeated at monthly intervals while the patient remains on bexarotene gel. Effective contraception must be used for one month prior to the initiation of therapy, during therapy and for at least one month following discontinuation of therapy; it is recommended that two reliable forms of contraception be used simultaneously unless abstinence is the chosen method. Male patients with sexual partners who are pregnant, possibly pregnant, or who could become pregnant must use condoms during sexual intercourse while applying bexarotene gel and for at least one month after the last dose of drug. Bexarotene gel therapy should be initiated on the second or third day of a normal menstrual period. No more than a one month supply of bexarotene gel should be given to the patient so that the results of pregnancy testing can be assessed and counseling regarding avoidance of pregnancy and birth defects can be reinforced.

AND PRECAUTIONS

• Hyperlipidemia: Bexarotene capsules cause elevations in blood lipids. Obtain baseline values, monitor, and manage elevations during therapy by dose reduction, interruption, discontinuation and/or lipid lowering therapy. ( 5.1 , 5.11 )
• Pancreatitis: Interrupt bexarotene capsules and evaluate if suspected. ( 5.2 )
• Hepatotoxicity, cholestasis, and hepatic failure: Interrupt or discontinue bexarotene capsules and evaluate if liver chemistry tests exceed three times the upper limit of normal values. ( 5.3 )
• Hypothyroidism: Bexarotene capsule therapy can cause hypothyroidism. Monitor and replace thyroid hormone if needed ( 5.5 )
• Neutropenia: Monitor for neutropenia. Reduce bexarotene capsule dose or interrupt as indicated. ( 5.6 )
• Photosensitivity: Minimize exposure to sunlight and artificial ultraviolet light during treatment. ( 5.10 )

5.1 Hyperlipidemia Bexarotene induces substantial elevations in lipids in most patients.

About

70% of patients with CTCL who received an initial dose of ≥300 mg/m 2 /day of bexarotene capsules had fasting triglyceride levels greater than 2.5 times the upper limit of normal.

About

55% had values over 800 mg/dL with a median of about 1200 mg/dL in those patients. Cholesterol elevations above 300 mg/dL occurred in approximately 60% and 75% of patients with CTCL who received an initial dose of 300 mg/m 2 /day or greater than 300 mg/m 2 /day, respectively. Decreases in high density lipoprotein (HDL) cholesterol to less than 25 mg/dL were seen in about 55% and 90% of patients receiving an initial dose of 300 mg/m 2 /day or greater than 300 mg/m 2 /day, respectively, of bexarotene capsules. Monitor lipid changes and treat abnormalities during therapy. The effects on triglycerides, HDL cholesterol, and total cholesterol were reversible with cessation of therapy, and could generally be mitigated by dose reduction and/or concomitant antilipemic therapy. Perform fasting blood lipid determinations before bexarotene capsule therapy is initiated and weekly until the lipid response to bexarotene is established, which usually occurs within two to four weeks, and monitor at eight week intervals thereafter. Fasting triglycerides should be normal or normalized with appropriate intervention prior to initiating bexarotene capsule therapy. Maintain triglyceride levels below 400 mg/dL to reduce the risk of clinical sequelae [ see Warnings and Precautions (5.2) ]. If fasting triglycerides are elevated or become elevated during treatment, institute antilipemic therapy, and if necessary, reduce or interrupt the dose of bexarotene capsules. In the 300 mg/m 2 /day initial dose group, 60% of patients were given lipid lowering drugs. Atorvastatin was used in 48% (73/152) of patients with CTCL. Because of a potential drug-drug interaction, avoid gemfibrozil use with bexarotene capsules [ see Drug Interactions (7) ].

5.2 Pancreatitis Acute pancreatitis, including a fatal case, has been reported in four patients with CTCL and in six patients with non-CTCL cancers treated with bexarotene capsules; the cases were associated with marked elevations of fasting serum triglycerides, the lowest being 770 mg/dL in one patient. One patient with advanced non-CTCL cancer died of pancreatitis. Interrupt bexarotene capsules and evaluate if pancreatitis is suspected. Patients with CTCL who have risk factors for pancreatitis (e.g., prior pancreatitis, uncontrolled hyperlipidemia, excessive alcohol consumption, uncontrolled diabetes mellitus, biliary tract disease, and medications known to increase triglyceride levels or to be associated with pancreatic toxicity) may be at greater risk for pancreatitis associated with bexarotene capsules [ see Warnings and Precautions (5.1) ].

5.3 Hepatotoxicity, cholestasis, and hepatic failure Bexarotene caused elevations in liver chemistry tests (LFTs) in 5% (AST), 2% (ALT), and 0% (bilirubin) in patients with CTCL receiving an initial dose of 300 mg/m 2 /day. In contrast, with an initial dose greater than 300 mg/m 2 /day of bexarotene capsules, the incidence of LFT elevations was higher at 7% (SGOT/AST), 9% (SGPT/ALT), and 6% (bilirubin). Two patients developed cholestasis, including one patient who died of liver failure. In clinical trials, elevated LFTs resolved within one month in 80% of patients following a decrease in dose or discontinuation of therapy. Obtain baseline LFTs and monitor LFTs after one, two and four weeks of treatment initiation, and if stable, at least every eight weeks thereafter during treatment. Interrupt or discontinue bexarotene capsules if test results exceed three times the upper limit of normal values for AST, ALT, or bilirubin.

5.4 Hypothyroidism Bexarotene induces hypothyroidism in about half of all patients treated by causing a reversible reduction in levels of thyroid hormone (total thyroxine [total T4]) and thyroid-stimulating hormone (TSH). The incidence of decreases in TSH and total T4 were about 60% and 45%, respectively, in patients with CTCL receiving an initial dose of 300 mg/m 2 /day. Hypothyroidism was reported as an adverse event in 29% of patients. Consider treatment with thyroid hormone supplementation in patients with hypothyroidism. In the 300 mg/m 2 /day initial dose group, 37% of patients were treated with thyroid hormone replacement. Obtain baseline thyroid function tests and monitor patients during treatment.

5.5 Neutropenia Leukopenia in the range of 1000 to <3000 WBC x 10 6 /L occurred in 18% of patients with CTCL receiving an initial dose of 300 mg/m 2 /day of bexarotene capsules. Patients receiving an initial dose greater than 300 mg/m 2 /day of bexarotene capsules had an incidence of leukopenia of 43%. No patient with CTCL treated with bexarotene capsules developed leukopenia of less than 1000 WBC x 10 6 /L. The usual time to onset of leukopenia was four to eight weeks after initiating bexarotene capsules. The leukopenia observed in most patients was predominately neutropenia. In the 300 mg/m 2 /day initial dose group, the incidence of NCI Grade 3 and Grade 4 neutropenia, respectively, was 12% and 4%. The leukopenia and neutropenia experienced during bexarotene capsule therapy resolved after dose reduction or discontinuation of treatment, on average within 30 days in 93% of the patients with CTCL and 82% of patients with non-CTCL cancers. Leukopenia and neutropenia were rarely associated with severe sequelae or serious adverse events. Obtain complete blood counts (CBC) at baseline and periodically during treatment.

5.6 Cataracts Posterior subcapsular cataracts occurred in preclinical toxicity studies in rats and dogs administered bexarotene capsules daily for 6 months. New cataracts or worsening of previous cataracts occurred in 15 of 79 patients who were monitored with serial slit lamp examinations. Because of the high prevalence and rate of cataract formation in older patient populations, the relationship of bexarotene capsules and cataracts cannot be determined in the absence of an appropriate control group. Patients treated with bexarotene capsules who experience visual difficulties should have an appropriate ophthalmologic evaluation.

5.7 Vitamin A Supplementation Hazard In clinical studies, patients were advised to limit vitamin A intake to ≤15,000 IU/day. Because of the relationship of bexarotene to vitamin A, patients should be advised to limit vitamin A supplements to avoid potential additive toxic effects.

5.8 Hypoglycemia Risk in Patients with Diabetes Mellitus In patients using insulin, agents enhancing insulin secretion (e.g., sulfonylureas), or insulin-sensitizers (e.g., thiazolidinedione class), based on the mechanism of action, bexarotene could enhance the action of these agents, resulting in hypoglycemia. Hypoglycemia has not been associated with the use of bexarotene capsules as monotherapy.

5.9 Photosensitivity Retinoids as a class have been associated with photosensitivity. In vitro assays indicate that bexarotene is a potential photosensitizing agent. Phototoxicity manifested as sunburn and skin sensitivity to sunlight occurred in patients who were exposed to direct sunlight while receiving bexarotene capsules. Advise patients to minimize exposure to sunlight and artificial ultraviolet light while receiving bexarotene capsules.

5.10 Laboratory Tests Before initiating bexarotene capsule therapy, obtain a CBC, fasting lipid profile, liver function tests, and a thyroid profile. Fasting triglycerides should be normal or normalized with appropriate intervention prior to therapy. Monitor lab tests during bexarotene capsule therapy as described above. Hyperlipidemia usually occurs within the initial two to four weeks. Therefore, weekly lipid determinations are recommended during this interval. Subsequently, in patients not hyperlipidemic, determinations can be performed less frequently [ see Warnings and Precautions (5.1 ) ]. A white blood cell count with differential should be obtained at baseline and periodically during treatment. Baseline liver function tests should be obtained and should be carefully monitored after one, two and four weeks of treatment initiation, and if stable, periodically thereafter during treatment. Baseline thyroid function tests should be obtained and then monitored during treatment as indicated [ see Warnings and Precautions ( 5.3 , 5.4 , 5.5 , 5.6 ) ].

5.11 Drug/Laboratory Test Interactions CA125 assay values in patients with ovarian cancer may be increased by bexarotene capsule therapy.