Drug Interaction Report

Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of modafinil (the racemate) and armodafinil (the R-enantiomer), which are both partially metabolized by the isoenzyme. Conversely, the plasma levels of some of these inhibitors may decrease, since many of them are also substrates of CYP450 3A4, and modafinil and armodafinil have been found to be modest inducers of CYP450 3A4. The clinical significance of this potential interaction is unknown. Clinical monitoring for altered effects of modafinil and armodafinil as well as the CYP450 3A4 inhibitor may be appropriate following addition or withdrawal of one or the other drug. Dose adjustments may be required if an interaction is suspected.

Administration with food may delay the absorption of modafinil (the racemate) and armodafinil (the R-enantiomer) without significantly affecting their overall bioavailability. According to the product labeling, modafinil's absorption may be delayed by approximately one hour if taken with food. Similarly, the time to reach peak plasma concentration (Tmax) of armodafinil may be delayed by approximately 2 to 4 hours in the fed state.

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.