Carbamazepine × Darunavir

Carbamazepine is a strong inducer of the CYP3A4 enzyme, and darunavir is cleared through CYP3A and is always given with a booster, ritonavir or cobicistat (darunavir SmPC). In a study of darunavir with ritonavir and carbamazepine 200 mg twice daily, carbamazepine exposure rose: area under the curve (AUC) by 45% and trough concentration by 54%, while the darunavir trough fell by 15% with an unchanged AUC (darunavir SmPC, 4.5). Darunavir boosted with cobicistat is more sensitive to CYP3A induction: strong inducers, carbamazepine among them, can lower cobicistat and darunavir concentrations to the point of lost antiviral effect, so the combination with cobicistat is contraindicated (darunavir SmPC, 4.3).

With ritonavir the main risk is carbamazepine toxicity from its higher concentration: drowsiness, dizziness, double vision, unsteadiness, nausea. With a cobicistat-based regimen the risk is loss of antiviral effect: rising viral load and darunavir resistance (darunavir SmPC, 4.3).

Management depends on the booster. Darunavir boosted with cobicistat, including fixed-dose tablets, is contraindicated with carbamazepine (darunavir SmPC, 4.3). With ritonavir no darunavir dose adjustment is needed; if the combination is necessary, the patient is monitored for carbamazepine adverse reactions, carbamazepine blood levels are checked and the dose is adjusted: by the darunavir SmPC the carbamazepine dose sometimes has to be reduced by 25–50% in this combination (darunavir SmPC, 4.5). The documents do not name a replacement antiepileptic; the treating physician chooses it by indication.