Drug Interaction Report

MONITOR: Coadministration with CYP450 inducers may decrease the plasma concentrations of zolpidem, which is primarily metabolized by CYP450 3A4 and, to a lesser extent, by CYP450 1A2. In eight healthy female volunteers, administration of a single 20 mg dose of zolpidem following pretreatment with the potent CYP450 inducer rifampin (600 mg/day for 5 days) decreased mean zolpidem peak plasma concentration (Cmax) and systemic exposure (AUC) by 58% and 73%, respectively, compared to administration following placebo. These changes were associated with significant reductions in the pharmacodynamic effects of zolpidem. In another study with 18 healthy volunteers, administration of a single 5 mg dose of zolpidem following daily dosing of carbamazepine 400 mg for 15 days resulted in a 41% decrease in mean Cmax and 57% decrease in mean AUC of zolpidem compared to administration of zolpidem alone.

MANAGEMENT: The potential for diminished pharmacologic effects of zolpidem should be considered during coadministration with CYP450 inducers, particularly potent ones like carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifamycins, and St. John's wort. Alternative treatments or a dosage adjustment for zolpidem may be required if an interaction is suspected.

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.

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

ADJUST DOSING INTERVAL: Administration of zolpidem with food may delay the onset of hypnotic effects. In 30 healthy subjects, administration of zolpidem 20 minutes after a meal resulted in decreased mean peak plasma drug concentration (Cmax) and area under the concentration-time curve (AUC) by 25% and 15%, respectively, compared to fasting. The time to reach peak plasma drug concentration (Tmax) was prolonged by 60%, from 1.4 to 2.2 hours.

MANAGEMENT: Patients receiving zolpidem should be advised to avoid the consumption of alcohol. For faster sleep onset, zolpidem should not be administered with or immediately after a meal.