Drug Interactions between fosphenytoin and mefloquine

GENERALLY AVOID: Mefloquine may increase the risk of seizures and decrease the effectiveness of anticonvulsant drugs in patients with epilepsy. The use of mefloquine alone and in combination with other related antimalarial agents (e.g., quinine, quinidine, chloroquine) has been associated with convulsions in some patients. Coadministration of mefloquine with certain anticonvulsant medications may also result in reduced seizure control by lowering the plasma levels of the anticonvulsant. In one case report, a patient with a seizure disorder previously well controlled on valproic acid and carbamazepine experienced several seizure episodes after taking mefloquine (250 mg weekly) for malaria prophylaxis. A subsequent kinetics study performed on the patient revealed a significant reduction in sodium valproate half-life (5.65 hours vs. reported normal of 8 to 20 hours) and no change in carbamazepine half-life. The author suggested that mefloquine be administered to epileptic patients with caution, particularly if being treated with sodium valproate. Additional clinical data with other antiepileptics are unavailable.

MANAGEMENT: According to the product labeling, mefloquine may precipitate convulsions in patients with a history of seizure disorder and should not be used for malaria prophylaxis in such patients. If mefloquine administration is required for curative treatment of malaria, anticonvulsant blood levels should be closely monitored and the anticonvulsant dosage adjusted accordingly as needed. Patients should be advised to notify their physician if they experience a loss of seizure control.

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.

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