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The following safety concerns are described elsewhere in the label:

• New or worsening heart failure [see WARNINGS AND PRECAUTIONS]
• Liver Injury [see WARNINGS AND PRECAUTIONS]
• Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see WARNINGS AND PRECAUTIONS]
• QT prolongation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

The safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is based on 5 placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of 6285 patients were randomized and treated, 3282 patients with MULTAQ (dronedarone tablets) 400 mg twice daily, and 2875 with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months.

In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ (dronedarone tablets) were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).

The most frequent adverse reactions observed with MULTAQ (dronedarone tablets) 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.

Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.

Table 1: Adverse Drug Reactions that Occurred in at Least 1% of Patients and Were More Frequent than Placebo

Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ (dronedarone tablets) .

The following laboratory data/ECG parameters were reported with MULTAQ (dronedarone tablets) 400 mg twice daily.

Table 2; Laboratory data/ECG parameters not necessarily reported as adverse events

Assessment of demographic factors such as gender or age on the incidence of treatment-emergent adverse events did not suggest an excess of adverse events in any particular sub-group.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of MULTAQ (dronedarone tablets) . Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac: Heart failure [see WARNINGS AND PRECAUTIONS]. Postmarketing cases of new onset and worsening heart failure have been reported during treatment with MULTAQ (dronedarone tablets) .

Hepatic: Serum hepatic enzymes and serum bilirubin increase: Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported [see WARNINGS AND PRECAUTIONS].

Dronedarone is metabolized primarily by CYP 3 A and is a moderate inhibitor of CYP 3 A and CYP 2D6 [see CLINICAL PHARMACOLOGY]. Dronedarone's blood levels can therefore be affected by inhibitors and inducers of CYP 3 A, and dronedarone can interact with drugs that are substrates of CYP 3 A and CYP 2D6.

Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6. It has the potential to inhibit P-glycoprotein (P-gP) transport.

Pharmacodynamic interactions can be expected with beta-blockers; calcium antagonists and digoxin.

In clinical trials, patients treated with dronedarone received concomitant medications including beta-blockers, digoxin, calcium antagonists (including those with heart rate-lowering effects), statins and oral anticoagulants.

Pharmacodynamic Interactions

Drugs prolonging the QT interval (inducing Torsade de Pointes)

Co-administration 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 [see CONTRAINDICATIONS].

Digoxin

Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). In clinical trials, increased levels of digoxin were observed when dronedarone was co-administered with digoxin. Gastrointestinal disorders were also increased. Because of the pharmacokinetic interaction and possible pharmacodynamic interaction, reconsider the need for digoxin therapy. 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 low doses 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 low dose of beta-blockers initially, and increase only after ECG verification of good tolerability.

Effects of Other Drugs on Dronedarone

Ketoconazole and other potent CYP 3A inhibitors

Repeated doses of ketoconazole, a strong CYP 3 A inhibitor, resulted in a 17-fold increase in dronedarone exposure and a 9-fold increase in Cmax. Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated [see CONTRAINDICATIONS].

Grapefruit juice

Grapefruit juice, a moderate inhibitor of CYP 3 A, resulted in a 3-fold increase in dronedarone exposure and a 2.5-fold increase in Cmax. Therefore, patients should avoid grapefruit juice beverages while taking MULTAQ (dronedarone tablets) .

Rifampin and other CYP 3A inducers

Rifampin decreased dronedarone exposure by 80%. Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John's wort with dronedarone because they decrease its exposure significantly.

Calcium channel blockers

Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure by approximately 1.4-to 1.7-fold.

Pantoprazole

Pantoprazole, a drug that increases gastric pH, did not have a significant effect on dronedarone pharmacokinetics.

Effects of Dronedarone on Other Drugs

Statins

Dronedarone increased simvastatin/simvastatin acid exposure by 4- and 2-fold, respectively. Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3 A and P-gP inhibitors such as dronedarone.

Calcium channel blockers

Dronedarone increases calcium channel blocker (verapamil, diltiazem or nifedipine) exposure by 1.4- to 1.5-fold.

Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range

Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3 A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.

Beta-blockers and other CYP 2D6 substrates

Dronedarone increased propranolol exposure by approximately 1.3-fold following single dose administration. Dronedarone increased metoprolol exposure by 1.6-fold following multiple dose administration. Other CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone.

P-glycoprotein substrates

Digoxin

Dronedarone increased digoxin exposure by 2.5-fold by inhibiting the P-gP transporter.

Dabigatran

Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone (1.7- to 2-fold).

Other P-gP substrates are expected to have increased exposure when co-administered with dronedarone.

Warfarin and losartan (CYP 2C9 substrates)

Losartan

No interaction was observed between dronedarone and losartan.

Warfarin

When healthy subjects were administered dronedarone 600 mg twice daily, exposure to S-warfarin was higher than when warfarin was administered alone (1.2-fold). Exposure to R-warfarin was unchanged and there were no clinically significant increases in INR.

More patients experienced clinically significant INR elevations ( ≥ 5) usually within 1 week after starting dronedarone vs. 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.

Theophylline (CYP 1A2 substrate)

Dronedarone does not increase steady state theophylline exposure.

Oral contraceptives

No decreases in ethinylestradiol and levonorgestrel concentrations were observed in healthy subjects receiving dronedarone concomitantly with oral contraceptives.

Last reviewed on RxList: 5/10/2011
This monograph has been modified to include the generic and brand name in many instances.