Drug Interactions between Cerebyx and emtricitabine / nelfinavir / tenofovir

GENERALLY AVOID: Coadministration with inducers of P-glycoprotein (P-gp) may decrease the oral bioavailability and plasma concentrations of tenofovir alafenamide (TAF), which is a substrate of the efflux transporter. In 26 healthy study subjects, administration of TAF (25 mg once daily) with the P-gp inducer carbamazepine (300 mg twice daily) decreased TAF plasma concentration (Cmax) and systemic exposure (AUC) by an average of 57% and 55%, respectively, compared to TAF administered alone. It is not known if, and to what extent, tenofovir disoproxil fumarate (TDF), another prodrug of tenofovir, may interact with P-gp inducers. The interaction has not been studied with TDF, and no information is found in the labeling of various products containing TDF, although it has been reported to be a P-gp substrate also.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of tenofovir alafenamide fumarate with P-gp inducers is not recommended. Whether this also applies to tenofovir disoproxil fumarate has not been established.

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MONITOR: Coadministration with nelfinavir may decrease the plasma concentrations of phenytoin. The proposed mechanism is nelfinavir induction of phenytoin metabolism via CYP450 2C9. In 12 study subjects, administration of phenytoin (300 mg once daily for 14 days) in combination with nelfinavir (1250 mg twice daily for 7 days) decreased mean phenytoin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 21%, 29% and 39%, respectively, compared to administration of phenytoin alone. The pharmacokinetics of nelfinavir were not significantly altered. The interaction was suspected in a case report of a 30-year-old HIV-infected patient receiving phenobarbital 100 mg and phenytoin 300 mg per day for generalized tonic-clonic seizures who experienced a seizure recurrence in association with approximately 50% reduced phenytoin levels following initiation of nelfinavir treatment. He had been stabilized on his anticonvulsant regimen for three years, and his last known seizure was 4 years prior to this episode. The seizure was controlled with diazepam 10 mg and phenytoin 100 mg.

MANAGEMENT: The potential for reduced therapeutic effects of phenytoin should be considered during coadministration with nelfinavir. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of nelfinavir in patients who are stabilized on their anticonvulsant regimen. No dosage adjustment for nelfinavir is recommended.

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