Drug Interaction Report

CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of elbasvir and grazoprevir, both of which are substrates of the isoenzyme. In 10 study subjects, administration of elbasvir 50 mg once daily with efavirenz 600 mg once daily decreased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 45%, 54% and 59%, respectively, compared to administration of elbasvir alone. Likewise, when grazoprevir 200 mg once daily and efavirenz 600 mg once daily were given together to 12 study subjects, grazoprevir Cmax, AUC and Cmin decreased by 87%, 83% and 69%, respectively. Efavirenz is generally considered a moderate inducer of CYP450 3A4. More potent inducers such as carbamazepine or phenytoin may interact to an even greater extent.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of elbasvir-grazoprevir with efavirenz or potent CYP450 3A4 inducers is considered contraindicated.

CONTRAINDICATED: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of elbasvir and grazoprevir, both of which are substrates of the isoenzyme. In 10 study subjects, administration of elbasvir 50 mg once daily with efavirenz 600 mg once daily decreased elbasvir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) by 45%, 54% and 59%, respectively, compared to administration of elbasvir alone. Likewise, when grazoprevir 200 mg once daily and efavirenz 600 mg once daily were given together to 12 study subjects, grazoprevir Cmax, AUC and Cmin decreased by 87%, 83% and 69%, respectively. Efavirenz is generally considered a moderate inducer of CYP450 3A4. More potent inducers such as carbamazepine or phenytoin may interact to an even greater extent.

MANAGEMENT: Given the risk of reduced viral susceptibility and resistance development associated with subtherapeutic antiviral drug levels, concomitant use of elbasvir-grazoprevir with efavirenz or potent CYP450 3A4 inducers 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.

Food does not appear to have clinically significant effects on the pharmacokinetics of elbasvir and grazoprevir. When a single 50 mg-100 mg dose of elbasvir-grazoprevir was administered to healthy study subjects with a high-fat meal (900 kcal; 500 kcal from fat), elbasvir peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 15% and 11%, respectively, while grazoprevir Cmax and AUC increased by 2.8- and 1.5-fold, respectively, compared to administration under fasting conditions. According to the product labeling, elbasvir-grazoprevir may be administered with or without food.