Modafinil

Effects of PROVIGIL on CYP3A4/5 Substrates The clearance of drugs that are substrates for CYP3A4/5 (e.g., steroidal contraceptives, cyclosporine, midazolam, and triazolam) may be increased by PROVIGIL via induction of metabolic enzymes, which results in lower systemic exposure. Dosage adjustment of these drugs should be considered when these drugs are used concomitantly with PROVIGIL [see Clinical Pharmacology ( 12.3 )] . The effectiveness of steroidal contraceptives may be reduced when used with PROVIGIL and for one month after discontinuation of therapy.

Alternative or concomitant methods of contraception are recommended for patients taking steroidal contraceptives (e.g., ethinyl estradiol) when treated concomitantly with PROVIGIL and for one month after discontinuation of PROVIGIL treatment. Blood levels of cyclosporine may be reduced when used with PROVIGIL. Monitoring of circulating cyclosporine concentrations and appropriate dosage adjustment for cyclosporine should be considered when used concomitantly with PROVIGIL.

Effects of PROVIGIL on CYP2C19 Substrates Elimination of drugs that are substrates for CYP2C19 (e.g., phenytoin, diazepam, propranolol, omeprazole, and clomipramine) may be prolonged by PROVIGIL via inhibition of metabolic enzymes, with resultant higher systemic exposure. In individuals deficient in the CYP2D6 enzyme, the levels of CYP2D6 substrates which have ancillary routes of elimination through CYP2C19, such as tricyclic antidepressants and selective serotonin reuptake inhibitors, may be increased by co-administration of PROVIGIL.

Dose adjustments of these drugs and other drugs that are substrates for CYP2C19 may be necessary when used concomitantly with PROVIGIL [see Clinical Pharmacology ( 12.3 )] . Warfarin More frequent monitoring of prothrombin times/INR should be considered whenever PROVIGIL is coadministered with warfarin [see Clinical Pharmacology ( 12.3 )] . Monoamine Oxidase (MAO) Inhibitors Caution should be used when concomitantly administering MAO inhibitors and PROVIGIL. Steroidal contraceptives (e.g., ethinyl estradiol): Use alternative or concomitant methods of contraception while taking PROVIGIL and for one month after discontinuation of PROVIGIL treatment.

( 7 ) Cyclosporine: Blood concentrations of cyclosporine may be reduced. ( 7 ) CYP2C19 substrates, such as omeprazole, phenytoin, and diazepam: Exposure of these medications may be increased. ( 7 )

8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of modafinil in pregnant women. Intrauterine growth restriction and spontaneous abortion have been reported in association with modafinil (a mixture of R- and S-modafinil) and armodafinil (the R-enantiomer of modafinil). Although the pharmacology of modafinil is not identical to that of the sympathomimetic amines, it does share some pharmacologic properties with this class. Certain of these drugs have been associated with intrauterine growth restriction and spontaneous abortions. Whether the cases reported with modafinil are drug-related is unknown.

In studies of modafinil and armodafinil conducted in rats (modafinil, armodafinil) and rabbits (modafinil), developmental toxicity was observed at clinically relevant plasma exposures. PROVIGIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Modafinil (50, 100, or 200 mg/kg/day) administered orally to pregnant rats throughout organogenesis caused, in the absence of maternal toxicity, an increase in resorptions and an increased incidence of visceral and skeletal variations in the offspring at the highest dose tested.

The higher no-effect dose for embryofetal developmental toxicity in rats (100 mg/kg/day) was associated with a plasma modafinil AUC less than that in humans at the recommended human dose (RHD) of PROVIGIL (200 mg/day). However, in a subsequent study of up to 480 mg/kg/day of modafinil, no adverse effects on embryofetal development were observed. Oral administration of armodafinil (60, 200, or 600 mg/kg/day) to pregnant rats throughout organogenesis resulted in increased incidences of fetal visceral and skeletal variations and decreased fetal body weight at the highest dose tested.

The highest no-effect dose for embryofetal developmental toxicity in rats (200 mg/kg/day) was associated with a plasma armodafinil AUC less than that in humans at the RHD of PROVIGIL. Modafinil administered orally to pregnant rabbits throughout organogenesis at doses of up to 100 mg/kg/day had no effect on embryofetal development; however, the doses used were too low to adequately assess the effects of modafinil on embryofetal development. In a subsequent developmental toxicity study evaluating doses of 45, 90, and 180 mg/kg/day in pregnant rabbits, the incidences of fetal structural alterations and embryofetal death were increased at the highest dose.

The highest no-effect dose for developmental toxicity (100 mg/kg/day) was associated with a plasma modafinil AUC similar to that…

8.3 Nursing Mothers It is not known whether modafinil or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROVIGIL is administered to a nursing woman.