Drug Interaction Report

CONTRAINDICATED: Coadministration of cobicistat with a drug that is both a substrate as well as a potent inducer of CYP450 3A4 may result in significantly decreased plasma concentrations of cobicistat and significantly increased concentrations of the other drug. Cobicistat is a substrate and a potent inhibitor of CYP450 3A4. In a study of 12 healthy volunteers, coadministration of the potent CYP450 3A4 inducer carbamazepine (200 mg twice daily) with cobicistat-elvitegravir (150 mg-150 mg once a day) reduced the cobicistat systemic exposure (AUC) and peak plasma concentration (Cmax) by 84% and 72%, respectively, and the elvitegravir AUC and Cmax by 69% and 45%, respectively. In addition, the AUC and Cmax of carbamazepine increased by 43% and 40%, respectively, due to inhibition of the CYP450 3A4-mediated metabolism by cobicistat.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic drug levels along with the risk of serious and/or life-threatening adverse effects associated with elevated plasma levels, the concomitant use of antiretroviral regimens containing cobicistat with potent CYP450 3A4 inducers that are also sensitive CYP450 3A4 substrates is considered contraindicated.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of carbamazepine. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

In a small, randomized, crossover study, the administration of carbamazepine with grapefruit juice (compared to water) increased plasma drug concentrations by approximately 40%. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

MANAGEMENT: Patients receiving carbamazepine should be advised to avoid or limit consumption of alcohol. Given the drug's narrow therapeutic index, patients receiving carbamazepine therapy should preferably avoid the regular consumption of grapefruits and grapefruit juice to prevent any undue fluctuations in plasma drug levels. Patients should be advised to report signs of carbamazepine toxicity (nausea, visual disturbances, dizziness, or ataxia) to their physicians.