Bexarotene

Effect of Other Drugs on TARGRETIN Gemfibrozil: Concomitant administration of TARGRETIN and gemfibrozil resulted in increases in plasma concentrations of bexarotene. Concomitant administration of gemfibrozil with TARGRETIN is not recommended. Effect of TARGRETIN on Other Drugs TARGRETIN 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 TARGRETIN 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 TARGRETIN therapy.

8.1 Pregnancy Risk Summary TARGRETIN, a retinoid, can cause fetal harm based on findings from animal studies when administered to a pregnant female and is contraindicated during pregnancy. Bexarotene was teratogenic and caused developmental mortality in rats following oral administration during organogenesis [see Data] . TARGRETIN must not be given to a pregnant female or a female who intends to become pregnant. If pregnancy does occur during treatment with TARGRETIN, immediately discontinue the drug and advise the pregnant female of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated populations is unknown.

However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Data Animal Data Bexarotene caused malformations when administered orally to pregnant rats during days 7-17 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. The plasma AUC of bexarotene in rats at 4 mg/kg/day is approximately one third the AUC in humans at the recommended daily dose. At doses greater than 10 mg/kg/day, bexarotene caused developmental mortality.

The no effect dose for fetal effects in rats was 1 mg/kg/day (producing an AUC approximately one sixth of the AUC at the recommended human daily dose).