Drug Interaction Report

GENERALLY AVOID: Use of milnacipran concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Inhibition of norepinephrine and serotonin reuptake by milnacipran can lead to cardiovascular effects including sustained increases in blood pressure and heart rate. However, effects of milnacipran in patients with significant hypertension, arrhythmia, or cardiac disease have not been systematically evaluated. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). No pharmacokinetic interaction was observed between milnacipran (200 mg/day) and digoxin (0.2 mg/day Lanoxicaps) following multiple-dose administration to healthy subjects.

MANAGEMENT: Coadministration of milnacipran and intravenous digoxin should be avoided. Caution is advised during coadministration with oral digoxin therapy. Blood pressure and heart rate should be measured prior to initiating milnacipran and periodically throughout treatment. A dosage reduction or discontinuation should be considered in patients who experience a sustained increase in blood pressure or heart rate while receiving milnacipran.

GENERALLY AVOID: Use of milnacipran in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Milnacipran alone can increase serum transaminase levels. In placebo-controlled fibromyalgia trials, increases in ALT were more frequently observed in patients treated with milnacipran 100 mg/day (6%) and 200 mg/day (7%) compared to patients treated with placebo (3%). One patient receiving milnacipran 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal (ULN) but did not exceed 10 times the ULN. Increases in AST were also more frequently observed in patients treated with milnacipran 100 mg/day (3%) and 200 mg/day (5%) than in patients treated with placebo (2%). There have been reported cases of increased liver enzymes and severe liver injury, including fulminant hepatitis, from foreign postmarketing experience with milnacipran. Significant underlying clinical conditions and/or use of multiple concomitant medications were present in the cases of severe liver injury.

MANAGEMENT: Due to the risk of liver injury, patients prescribed milnacipran should be counseled to avoid excessive use of alcohol. Milnacipran should generally not be prescribed to patients with substantial alcohol use.

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.