Drug Interaction Report

MONITOR: Rufinamide may modestly or moderately decrease the plasma concentrations and therapeutic effects of drugs that are CYP450 3A4 substrates. The mechanism is enhanced metabolism by CYP450 3A4 enzyme induction. Enzyme induction is more pronounced with larger doses of rufinamide. After treatment with rufinamide 400 mg twice daily for 11 days, the clearance of triazolam was increased by 55% and the exposure was decreased by 36%.

MANAGEMENT: During concomitant treatment with rufinamide and drugs that are CYP450 3A4 substrates, it is recommended that patients should be monitored for 2 weeks when rufinamide is added to or withdrawn from therapy, or after increases of the dose. Dose adjustments of the coadministered drug may be required if an interaction is suspected. The manufacturer also recommends that monitoring should be considered during concomitant use of drugs with a narrow therapeutic index, including digoxin and warfarin.

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

ADJUST DOSING INTERVAL: Food enhances the oral absorption and bioavailability of rufinamide. In healthy volunteers, administration of a single 400 mg dose of rufinamide with food resulted in an approximately 56% increase in mean peak plasma concentration (Cmax) and a 34% increase in systemic exposure (AUC) compared to administration during a fasting state.

MANAGEMENT: To ensure maximal oral absorption, it is preferable to administer rufinamide with food. Patients receiving rufinamide should be advised to avoid consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how rufinamide affects them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Administration of digoxin with a high-fiber meal has been shown to decrease its bioavailability by almost 20%. Fiber can sequester up to 45% of the drug when given orally. Patients should be advised to maintain a regular diet without significant fluctuation in fiber intake while digoxin is being titrated.

Grapefruit juice may modestly increase the plasma concentrations of digoxin. The mechanism is increased absorption of digoxin due to mild inhibition of intestinal P-glycoprotein by certain compounds present in grapefruits. In 12 healthy volunteers, administration of grapefruit juice with and 30 minutes before, as well as 3.5, 7.5, and 11.5 hours after a single digoxin dose (0.5 mg) increased the mean area under the plasma concentration-time curve (AUC) of digoxin by just 9% compared to administration with water. Moreover, P-glycoprotein genetic polymorphism does not appear to influence the magnitude of the effects of grapefruit juice on digoxin. Thus, the interaction is unlikely to be of clinical significance.