Dronedaroneinteractions

Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A and CYP2D6 and has potentially important pharmacodynamic interactions

Class I or III antiarrhythmics: Contraindicated.

Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor digoxin levels.

Calcium channel blockers (CCB): Initiate CCB with low dose and increase after ECG verification of tolerability.

Beta-blockers: May provoke excessive bradycardia. Initiate with low dose and increase after ECG verification of tolerability.

CYP3A inducers: Avoid concomitant use.

Grapefruit juice: Avoid concomitant use.

Statins: Avoid simvastatin doses greater than 10 mg daily. Follow label recommendations for concomitant use of other statins with a CYP3A and P-gp inhibitor like dronedarone.

CYP3A substrates with a narrow therapeutic index (e.g., sirolimus and tacrolimus): Monitor and adjust dosage of concomitant drug as needed when used with MULTAQ.

Warfarin: Monitor INR after initiating dronedarone in patients taking warfarin.

7.1 Pharmacodynamic

Interactions Drugs Prolonging the QT Interval (Inducing Torsade de Pointes) Coadministration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of torsade de pointes–type ventricular tachycardia. Digoxin In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone versus placebo groups. Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity. Calcium Channel Blockers Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone's effects on conduction. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability. Beta-Blockers In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers. Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.

7.2 Effects of

Other Drugs on Dronedarone Ketoconazole and Other Potent CYP3A Inhibitors Concomitant use of ketoconazole as well as other potent CYP3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased. Grapefruit Juice Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased. Rifampin and Other CYP3A Inducers Avoid rifampin or other CYP3A inducers such as phenobarbital, carbamazepine, phenytoin, and St. John's wort because they decrease exposure to dronedarone significantly. Calcium Channel Blockers Verapamil and diltiazem are moderate CYP3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability.

7.3 Effects of

Dronedarone on Other Drugs Simvastatin Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin. Other Statins Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP3A and P-gp inhibitors such as dronedarone. Calcium Channel Blockers Dronedarone increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine). Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability. Sirolimus, Tacrolimus, and Other CYP3A Substrates with Narrow Therapeutic Range Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately. Beta-Blockers and Other CYP2D6 Substrates Dronedarone increased the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. Other CYP2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon coadministration with dronedarone. P-glycoprotein Substrates Digoxin Dronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity. Dabigatran Dronedarone increases dabigatran plasma exposures by inhibiting the P-gp transporter. In patients with moderate renal impairment (CrCL 30–50 mL/min), reduce the dose of dabigatran to 75 mg twice daily when concomitantly administered with dronedarone. In patients with severe renal impairment (CrCL 15–30 mL/min), concomitant use of dronedarone with dabigatran should be avoided. Warfarin When coadministered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR. More patients experienced clinically significant INR elevations (≥5) usually within 1 week after starting dronedarone versus placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group. Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin.