Drug Interaction Report

MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of mirtazapine, which is partially metabolized by the isoenzyme. In healthy study subjects, administration of mirtazapine (30 mg once daily) with the potent CYP450 3A4 inducer carbamazepine (400 mg twice daily) decreased mean steady-state mirtazapine peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 40% and 60%, respectively, compared to administration with placebo. In another study consisting of patients with unipolar depression receiving mirtazapine 45 mg daily, the addition of carbamazepine reportedly decreased mirtazapine plasma concentrations by approximately 47% after 3 weeks. Likewise, when mirtazapine 30 mg once daily was given with phenytoin 200 mg once daily in healthy, nonsmoking male volunteers, steady-state mirtazapine Cmax and AUC decreased by 33% and 47%, respectively, compared to mirtazapine given alone. Mirtazapine had no significant effect on the pharmacokinetics of either carbamazepine or phenytoin.

MANAGEMENT: The possibility of diminished therapeutic response to mirtazapine should be considered during coadministration with CYP450 3A4 inducers, particularly potent ones like carbamazepine, enzalutamide, lumacaftor, mitotane, phenobarbital, phenytoin, rifampin, and St. John's wort. Pharmacologic response to mirtazapine should be monitored more closely whenever a CYP450 3A4 inducer is added to or withdrawn from therapy, and the dosage adjusted as necessary.

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 CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.