Bexarotene Drug Information

Bexarotene gel, 1% is indicated for the topical treatment of cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies.

Bexarotene gel, 1% should be initially applied once every other day for the first week. The application frequency should be increased at weekly intervals to once daily, then twice daily, then three times daily and finally four times daily according to individual lesion tolerance. Generally, patients were able to maintain a dosing frequency of two to four times per day.

Most responses were seen at dosing frequencies of two times per day and higher. If application site toxicity occurs, the application frequency can be reduced. Should severe irritation occur, application of drug can be temporarily discontinued for a few days until the symptoms subside.

See CONTRAINDICATIONS: Pregnancy. Sufficient gel should be applied to cover the lesion with a generous coating. The gel should be allowed to dry before covering with clothing.

Because unaffected skin may become irritated, application of the gel to normal skin surrounding the lesions should be avoided. In addition, do not apply the gel near mucosal surfaces of the body. A response may be seen as soon as four weeks after initiation of therapy but most patients require longer application.

With continued application, further benefit may be attained. The longest onset time for the first response among the responders was 392 days based on the Composite Assessment of Index Lesion Severity in the multicenter study. In clinical trials, bexarotene gel, 1% was applied for up to 172 weeks.

Bexarotene gel, 1% should be continued as long as the patient is deriving benefit. Occlusive dressings should not be used with bexarotene gel, 1%. Bexarotene GEL, 1% IS A TOPICAL THERAPY AND IS NOT INTENDED FOR SYSTEMIC USE.

Bexarotene GEL, 1% HAS NOT BEEN STUDIED IN COMBINATION WITH OTHER CTCL THERAPIES.

The safety of bexarotene gel has been assessed in clinical studies of 117 patients with CTCL who received bexarotene gel for up to 172 weeks. In the multicenter open-label study, 50 patients with CTCL received bexarotene gel for up to 98 weeks. The mean duration of therapy for these 50 patients was 199 days.

The most common adverse events reported with an incidence at the application site of at least 10% in patients with CTCL were rash, pruritus, skin disorder, and pain. Adverse events leading to dose reduction or study drug discontinuation in at least two patients were rash, contact dermatitis, and pruritus. There were 12 patients (24%) who experienced at least one moderately severe adverse event.

Only one patient (2%) experienced a severe adverse event (rash). In the patients with CTCL receiving bexarotene gel, adverse events reported regardless of relationship to study drug at an incidence of ≥5% are presented in Table 1. A similar safety profile for bexarotene gel was demonstrated in the Phase I-II program.

As in the multicenter study, the most common adverse events regardless of relationship to study drug in the Phase I-II program were rash (78%), pain (40%), and pruritus (40%). To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.com

DRUG-DRUG INTERACTIONS Patients who are applying bexarotene gel should not concurrently use products that contain DEET ( N,N -diethyl- m -toluamide), a common component of insect repellent products. An animal toxicology study showed increased DEET toxicity when DEET was included as part of the formulation. No formal studies to evaluate drug interactions with bexarotene have been conducted.

Bexarotene oxidative metabolites appear to be formed through cytochrome P450 3A4. On the basis of the metabolism of bexarotene by cytochrome P450 3A4, concomitant ketoconazole, itraconazole, erythromycin and grapefruit juice could increase bexarotene plasma concentrations. Similarly, based on data that gemfibrozil increases bexarotene concentrations following oral bexarotene administration, concomitant gemfibrozil could increase bexarotene plasma concentrations.

However, due to the low systemic exposure to bexarotene after low to moderately intense gel regimens (see CLINICAL PHARMACOLOGY ), increases that occur are unlikely to be of sufficient magnitude to result in adverse effects. No drug interaction data are available on concomitant administration of bexarotene gel and other CTCL therapies.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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.

Systemic toxicity following acute overdosage with topical application of bexarotene gel is unlikely because of low systemic plasma levels observed with normal therapeutic doses. There is no specific antidote for overdosage. There has been no experience with acute overdose of bexarotene gel in humans.

Any overdose with bexarotene gel should be treated with supportive care for the signs and symptoms exhibited by the patient.