Drug Interactions between carbamazepine and lopinavir / ritonavir

ADJUST DOSING INTERVAL: Coadministration of lopinavir-ritonavir with carbamazepine may result in decreased plasma concentrations of lopinavir and increased plasma concentrations of carbamazepine. The proposed mechanism involves carbamazepine induction of lopinavir metabolism via CYP450 3A4 and conversely, lopinavir-ritonavir inhibition of carbamazepine metabolism via the same enzymatic pathway. Clinical studies have shown that potent CYP450 3A4 inducers can significantly alter the plasma concentrations of lopinavir, possibly by overriding some of the boosting effects of ritonavir and enhancing the clearance of both lopinavir and ritonavir. In 12 healthy volunteers, administration of lopinavir-ritonavir (400 mg-100 mg twice daily for 22 days) with potent CYP450 3A4 inducer phenytoin (300 mg once daily on days 11 through 22) decreased lopinavir peak plasma concentration (Cmax), systemic exposure (AUC), and trough plasma concentration (Cmin) by 24%, 33%, and 46%, respectively. Ritonavir Cmax, AUC, and Cmin were also reduced by 20%, 28%, and 47%, respectively, although only the change in Cmin was statistically significant. In addition, in one case report a 50-year-old HIV-positive male who had been stabilized on carbamazepine (400 mg three times a day), developed excessive drowsiness within 9 days of starting an antiretroviral regimen containing lopinavir-ritonavir (400 mg-100 mg twice daily), tenofovir, and lamivudine. The carbamazepine serum concentration was found to have increased from a pre-antiretroviral treatment level of 10.3 mg/L, up to 15 mg/L by day 9 of the concomitant antiretroviral treatment regimen. However, symptoms resolved when the carbamazepine dose was reduced to 400 mg twice daily, and carbamazepine serum concentrations measured on day 11 had fallen to 7.4 mg/L.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiretroviral drug levels, caution is advised if lopinavir-ritonavir is prescribed with carbamazepine. Once-daily administration of lopinavir-ritonavir should be avoided when used concomitantly with carbamazepine. An increase in the dosage of lopinavir-ritonavir may be necessary, although dosage adjustment has not been evaluated in clinical studies. Close clinical and laboratory monitoring of antiretroviral response is recommended following the addition or discontinuation of carbamazepine in patients already receiving lopinavir-ritonavir as part of their HIV treatment regimen. Likewise, if lopinavir-ritonavir is added to stable carbamazepine therapy, serum drug levels and pharmacologic effects should be closely monitored and the carbamazepine dose adjusted accordingly. Patients should be advised to contact their doctor if they develop signs of carbamazepine toxicity such as ataxia, disorientation, dizziness, nausea, vomiting, and visual disturbances.

MONITOR: Coadministration with ritonavir may significantly increase the plasma concentrations and pharmacologic effects of carbamazepine. The proposed mechanism is ritonavir inhibition of CYP450 3A4, the isoenzyme responsible for the metabolic clearance of carbamazepine. There have been case reports of patients stabilized on carbamazepine therapy who developed ataxia, disorientation, vertigo, vomiting, and transient liver dysfunction following the addition of ritonavir, subsequently requiring discontinuation of ritonavir or substantial reductions of carbamazepine dosage. The effect of carbamazepine on ritonavir clearance has not been reported. Theoretically, ritonavir plasma levels may decrease due to carbamazepine induction of CYP450 3A4, which also metabolizes ritonavir.

MANAGEMENT: Given its narrow therapeutic index, caution is advised if carbamazepine must be used concomitantly with ritonavir. Carbamazepine 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. Patients should be advised to contact their physician if they develop signs of carbamazepine toxicity such as ataxia, dizziness, nausea, vomiting, and visual disturbances. In addition, it may be appropriate to monitor patients for potentially reduced antiretroviral response due to decreased plasma levels of ritonavir and other antiretroviral agents induced by carbamazepine.