Drug Interaction Report

MONITOR CLOSELY: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of mefloquine, which is primarily metabolized by the isoenzyme. In seven healthy, nonsmoking male volunteers, administration of a single 500 mg oral dose of mefloquine on day 7 of treatment with the potent CYP450 3A4 inducer rifampin (600 mg orally once daily on days 1 through 7, followed by 600 mg twice weekly on days 8 through 56) decreased mean mefloquine peak plasma concentration (Cmax) and systemic exposure (AUC) by 19% and 68%, respectively, compared to mefloquine administered alone. The mean elimination half-life of mefloquine was also decreased by 63% (from 305 to 113 hours) in the presence of rifampin, while mean apparent oral clearance increased by 281%.

MANAGEMENT: The possibility of diminished antimalarial efficacy should be considered when mefloquine is used in combination with potent CYP450 3A4 inducers. Alternative agents with minimal or less enzyme induction potential are recommended when possible to avoid the risk of therapeutic failure, particularly in the treatment of acute malaria infections.

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of mefloquine. The proposed mechanism is increased drug solubility in the presence of food. In 20 healthy volunteers, administration of a single 750 mg oral dose of mefloquine 30 minutes following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of mefloquine by 73% and 40%, respectively, compared to administration in the fasting state. The Cmax and AUC of the carboxylic acid metabolite were also increased by 35% and 33%, respectively, compared to fasting. In addition, the time to reach peak plasma concentration (Tmax) of mefloquine was significantly shorter after food intake (17 hours) than in the fasting state (36 hours). There was no difference in the elimination half-life of mefloquine and metabolite, or the Tmax for the metabolite.

MANAGEMENT: To ensure maximal oral absorption, mefloquine should be administered immediately after a meal with at least 8 ounces of water.

ADJUST DOSING INTERVAL: Administration with food may increase the oral bioavailability of rifapentine and reduce the incidence of gastrointestinal adverse events. Administration with a high fat meal typically increases rifapentine's maximum concentration (Cmax) and systemic exposure (AUC) by approximately 40% to 50% over that observed when rifapentine is administered under fasting conditions. Rifapentine is often prescribed in combination with isoniazid. When single doses of rifapentine (900 mg) and isoniazid (900 mg) were administered with a low fat, high carbohydrate breakfast, the Cmax and AUC of rifapentine increased by 47% and 51%, respectively. On the other hand, isoniazid's Cmax and AUC decreased by 46% and 23%, respectively.

MANAGEMENT: Products containing oral rifapentine as the sole ingredient recommend administration with a meal to increase bioavailability and reduce the occurrence of gastrointestinal upset, nausea, and/or vomiting. Consultation of product labeling for combination products and/or relevant guidelines may be helpful if rifapentine is combined with a medication that is typically taken on an empty stomach.