Drug Interaction Report

MONITOR CLOSELY: Coadministration with inhibitors of organic cation transporter 2 (OCT2) may increase the plasma concentrations of dalfampridine. In vitro studies have shown that OCT2 is the primary transporter responsible for the active tubular secretion of dalfampridine, which accounts for approximately 60% of its renal elimination--the major route of clearance for dalfampridine. When a single 10 mg dose of dalfampridine was administered to 23 healthy volunteers with the OCT2 inhibitor cimetidine (400 mg every 6 hours), dalfampridine systemic exposure (AUC) was 25% higher relative to the reference value. Elevated plasma levels of dalfampridine may increase the risk of adverse effects, particularly seizures.

MANAGEMENT: Caution and assessment of the potential benefits against the risk of seizures should be considered if dalfampridine is used concurrently with OCT2 inhibitors. Some international product labeling considers concomitant use to be contraindicated. Individual product labeling should be consulted for both dalfampridine and the coadministered OCT2 inhibitor for more specific guidance.

Concurrent use of cimetidine and ethanol may result in increased ethanol concentrations. The mechanism appears to be due to inhibition of gastric alcohol dehydrogenase by cimetidine, leading to increased bioavailability of the alcohol and inhibition of hepatic metabolism of alcohol. The clinical significance of this interaction is limited. More importantly, patients requiring cimetidine for gastrointestinal disease should be counseled to avoid alcohol to prevent worsening of their disease. The other H-2 receptor antagonists appear to have minimal effects on the concentrations of alcohol.

Caffeine effects may be increased in patients also taking cimetidine. The mechanism may be due to decreased caffeine metabolism induced by cimetidine. Although adequate clinical data are lacking, a reduction in dose or elimination of caffeine may be needed if excess CNS stimulation is observed.

H2 antagonists may reduce the clearance of nicotine. Cimetidine, 600 mg given twice a day for two days, reduced clearance of an intravenous nicotine dose by 30%. Ranitidine, 300 mg given twice a day for two days, reduced clearance by 10%. The clinical significance of this interaction is not known. Patients should be monitored for increased nicotine effects when using the patches or gum for smoking cessation and dosage adjustments should be made as appropriate.