Drug Interaction Report

MONITOR: Coadministration of mirtazapine with drugs that inhibit one or more of its metabolic pathways may result in increased plasma concentrations of mirtazapine. In vitro data from human liver microsomes indicate that CYP450 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite, while CYP450 3A4 is primarily responsible for the formation of the N-desmethyl and N-oxide metabolites. When cimetidine, a weak inhibitor of CYP450 1A2, 2D6 and 3A4, was given at 800 mg twice daily for 14 days to twelve healthy male subjects in combination with mirtazapine 30 mg once daily on days 6 to 12, mean steady-state mirtazapine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 22% and 54%, respectively. Mirtazapine had no effect on the pharmacokinetics of cimetidine. In another study with 24 healthy male Caucasian subjects, administration of the potent CYP450 3A4 inhibitor ketoconazole at 200 mg twice daily for 6.5 days increased Cmax and AUC of a single 30 mg dose of mirtazapine by approximately 40% and 50%, respectively. A case report described increases in serum mirtazapine concentrations of three- to fourfold in two patients following the addition of fluvoxamine, a potent CYP450 1A2 and weak CYP450 2D6/3A4 inhibitor. One patient reported feeling more anxious with the combination.

MANAGEMENT: The possibility of prolonged and/or increased pharmacologic effects of mirtazapine should be considered during coadministration of drugs that inhibit CYP450 1A2, 2D6 and/or 3A4. Therapeutic response to mirtazapine should be monitored more closely following initiation, discontinuation, or dosing change of CYP450 inhibitors, and the mirtazapine dosage adjusted as necessary. A prolonged duration of monitoring for adverse effects may be required depending on the elimination half-life of the concomitant drug. For example, it should be noted that rolapitant, a moderate CYP450 2D6 inhibitor, can increase plasma concentrations and the risk of adverse effects of mirtazapine for at least 28 days after administration of rolapitant.

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.

ADJUST DOSING INTERVAL: Food may reduce the systemic bioavailability of amprenavir from fosamprenavir oral suspension. The mechanism of interaction has not been described. According to the product labeling, administration of fosamprenavir oral suspension (1400 mg single dose) with a high-fat meal (967 kcal, 67 g fat, 33 g protein, 58 g carbohydrate) reduced amprenavir peak plasma concentration (Cmax) by 46% and systemic exposure (AUC) by 28% compared to administration in a fasted state. The time to reach peak plasma level (Tmax) was delayed by 0.72 hours. In contrast, the same high-fat meal did not affect the pharmacokinetics of amprenavir from fosamprenavir tablets.

MANAGEMENT: Fosamprenavir suspension should be administered on an empty stomach in adults, but with food in pediatric patients to aid palatability and compliance. If emesis occurs within 30 minutes after dosing the suspension, the dose should be repeated. Fosamprenavir tablets may be taken with or without food.