Drug Interactions between fosphenytoin and Paxlovid

CONTRAINDICATED: Coadministration with drugs that are potent inducers of CYP450 3A4 may decrease the plasma concentrations of nirmatrelvir and result in a potential loss of virologic response. The proposed mechanism is increased clearance due to induction of CYP450 3A4, which is the isoenzyme primarily responsible for the metabolism of nirmatrelvir. According to the manufacturer, coadministration of nirmatrelvir-ritonavir (300 mg-100 mg twice daily for 5 doses) with the potent CYP450 3A4 inducer carbamazepine (300 mg twice daily for 16 doses) (n=9) decreased the systemic exposure (AUC) and peak plasma concentration (Cmax) of nirmatrelvir by approximately 55% and 43%, respectively. Data are unavailable for other, less potent inducers. In addition, the plasma concentrations and pharmacologic effects of the concomitant inducer may be affected; however, clinical data are lacking.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of nirmatrelvir-ritonavir with drugs that are potent inducers of CYP450 3A4 is considered to be contraindicated.

MONITOR: Coadministration of ritonavir and phenytoin may result in decreased plasma concentrations of both drugs. The proposed mechanism involves ritonavir induction of phenytoin metabolism via CYP450 2C9 and, conversely, phenytoin induction of ritonavir metabolism via CYP450 3A4. Data are limited. In one case report, serum phenytoin levels in a patient receiving carbamazepine (1200 mg/day), phenytoin (500 mg/day), and phenobarbital (250 mg/day) declined 30% following initiation of antiretroviral therapy containing ritonavir (300 mg twice a day). In another case, a patient receiving carbamazepine (600 mg/day) and phenytoin (400 mg/day) was started on ritonavir (600 mg twice daily) with no apparent change in serum phenytoin levels. In a pharmacokinetic study of 8 healthy volunteers, administration of phenytoin (300 mg once daily for 22 days) in combination with lopinavir-ritonavir (400 mg-100 mg twice a day on days 12 thru 22) decreased phenytoin peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 28%, 31% and 34%, respectively, compared to administration of phenytoin alone. In a different arm of the same study, Cmax, AUC and Cmin of lopinavir decreased by 24%, 33% and 46%, respectively, when lopinavir-ritonavir (400 mg-100 mg twice a day for 22 days) was coadministered with phenytoin (300 mg once daily on days 11 through 22) in 12 healthy subjects. Ritonavir Cmax, AUC and Cmin were also reduced by 20%, 28% and 47%, respectively, although only the change in Cmin was statistically significant.

MANAGEMENT: The potential for reduced therapeutic effects of phenytoin should be considered during coadministration with ritonavir. Phenytoin serum levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation or discontinuation of ritonavir in patients who are stabilized on their anticonvulsant regimen. In addition, it may be necessary to monitor patients for potentially reduced antiretroviral response due to decreased plasma levels of ritonavir and other antiretroviral agents induced by phenytoin.