Coadministration is contraindicated. Decreased plasma concentrations of nirmatrelvir/ritonavir may lead to loss of virologic response and possible resistance. Carbamazepine is strong CYP3A4 inducer, and this may lead to a decreased exposure of nirmatrelvir and ritonavir and potential loss of virologic response. Coadministration of carbamazepine (300 mg twice daily for 16 doses) and nirmatrelvir/ritonavir (300/100 mg twice daily for 5 doses) was studied in 9 subjects. Nirmatrelvir Cmax and AUC decreased by 43% and 55%.

Coadministration of carbamazepine (300 mg twice daily for 16 doses) and nirmatrelvir/ritonavir (300/100 mg twice daily for 5 doses) was studied in 9 subjects. Nirmatrelvir Cmax and AUC decreased by 43% and 55%. Paxlovid is contraindicated with drugs that are potent CYP3A inducers where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance. Paxlovid cannot be started immediately after discontinuation of carbamazepine due to the delayed offset of the recently discontinued CYP3A inducer.

The effect of carbamazepine (a strong CYP3A4 inducer) on the pharmacokinetics of nirmatrelvir/ritonavir (300/100 mg twice daily for 5 doses) was investigated in a two phase 1, open-label, fixed-sequence study in 10 healthy adults. During the carbamazepine phase of the study, carbamazepine was administered at doses of 100 mg twice daily on days 1-3; 200 mg twice daily on days 4-7 to improve tolerability; and at 300 mg twice daily from days 8-15. Coadministration of carbamazepine at the 300 mg twice daily dose decreased single-dose nirmatrelvir AUC and Cmax by 55% and 43%; ritonavir AUC and Cmax decreased by 83% and 74%. No serious or severe adverse events were reported. Exposures of nirmatrelvir were significantly lower when coadministered with carbamazepine likely due to the induction effect of carbamazepine on intestinal or hepatic CYP3A.Therefore, administration of nirmatrelvir/ritonavir is contraindicated with potent CYP3A4 inducers like carbamazepine, due to both the differential effects of the inducer on the PK of nirmatrelvir and ritonavir and the risk that the lower trough concentration or Cmin values of nirmatrelvir may negatively affect its efficacy and possibly contribute to virologic resistance. Furthermore, since it takes several days for CYP3A4 induction to dissipate, stopping the inducer to start treatment with nirmatrelvir/ritonavir should not be considered a viable option.