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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]
- Pulmonary toxicity [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 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 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 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
|Dronedarone 400 mg twice daily
|Dyspeptic signs and symptoms||1%||2%|
|Skin and subcutaneous tissue|
|Including rashes (generalized, macular, maculo-papular, erythematous), pruritus, eczema, dermatitis, dermatitis allergic||3%||5%|
Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.
The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily.
Table 2: Laboratory data/ECG
parameters not necessarily reported as adverse events
|Placebo||MULTAQ 400 mg twice daily|
|Early increases in creatinine ≥ 10%||21%||51%|
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.
The following adverse reactions have been identified during post-approval use of MULTAQ. 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.
Hepatic: Liver Injury [see WARNINGS AND PRECAUTIONS]
Immune: Anaphylactic reactions including angioedema
Vascular: Vasculitis, including leukocytoclastic vasculitis
Read the Multaq (dronedarone tablets) Side Effects Center for a complete guide to possible side effects
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, CLINICAL PHARMACOLOGY].
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 vs. placebo groups. [See Clinical Trials].
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 [see CLINICAL PHARMACOLOGY].
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 [see CLINICAL PHARMACOLOGY].
Effects Of Other Drugs On Dronedarone
Ketoconazole and other potent CYP 3A inhibitors
Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].
Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased [see CLINICAL PHARMACOLOGY].
Rifampin and other CYP 3A inducers
Calcium channel blockers
Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see CLINICAL PHARMACOLOGY].
Effects Of Dronedarone On Other Drugs
Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin [see CLINICAL PHARMACOLOGY].
Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A 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 [see CLINICAL PHARMACOLOGY].
Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range
Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A 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 the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. 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 [see CLINICAL PHARMACOLOGY].
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 [see CLINICAL PHARMACOLOGY].
Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone.
Other P-gp substrates are expected to have increased exposure when co-administered with dronedarone.
When co-administered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR [see CLINICAL PHARMACOLOGY].
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.
Read the Multaq Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 2/10/2014
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