Drug Interaction Report

ADJUST DOSE: Coadministration with daclatasvir may increase the serum concentrations of digoxin. The proposed mechanism is daclatasvir inhibition of the P-glycoprotein-mediated renal tubular secretion of digoxin. When 0.125 mg once daily of digoxin was administered with 60 mg once daily daclatasvir, digoxin peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 65% and 27%, respectively.

MANAGEMENT: Serum digoxin levels and pharmacologic effects should be closely monitored following the addition or withdrawal of daclatasvir, and the digoxin dosage adjusted as needed. Patients already receiving daclatasvir who are initiating digoxin should start at the lowest appropriate digoxin dosage, with further adjustments based on serum digoxin levels and clinical response. Patients already receiving digoxin prior to initiating daclatasvir should have serum digoxin levels taken before starting daclatasvir, then have digoxin levels lowered by reducing dosage approximately 30% to 50% or by modifying the dosing frequency with continued monitoring. Patients should be advised to seek medical attention if they experience signs of digoxin toxicity such as nausea, anorexia, visual disturbances, slow pulse, or irregular heartbeat.

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.