MULTAQ SAFETY PROFILE

The most frequent adverse reactions observed with MULTAQ 400 mg bid were diarrhea, nausea, abdominal pain, vomiting, and asthenia.1

Adverse reactions ≥1% and greater than placebo observed in pooled data from 5 placebo-controlled trials1

  Placebo
(N=2875)
MULTAQ
400 mg bid
(N=3282)
GASTROINTESTINAL DISORDERS    
Diarrhea 6% 9%
Nausea 3% 5%
Abdominal Pain 3% 4%
Vomiting 1% 2%
Dyspeptic signs and symptoms 1% 2%
GENERAL DISORDERS    
Asthenic conditions 5% 7%
CARDIAC DISORDERS    
Bradycardia 1% 3%
SKIN AND SUBCUTANEOUS-TISSUE DISORDERS    
Including rashes (generalized, macular, maculopapular,
erythematous), pruritus, eczema, dermatitis allergic
3% 5%

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

Discontinuation

  • In clinical trials, premature discontinuation due to adverse reactions occurred in1
    • - 11.8% of the MULTAQ-treated patients
    • - 7.7% of the placebo-treated patients
  • Most common reasons for discontinuation of therapy with MULTAQ and placebo1
    • - Gastrointestinal disorders (3.2% vs 1.8%)
    • - QT prolongation (1.5% vs 0.5%)

Adverse events in the EURIDIS/ADONIS trials2

EVENT Placebo
(N=409)
MULTAQ
(N=828)
P-Value
DEATH n (%)      
Any cause 3 (0.7) 8 (1.0) 1.00
Sudden death 1 (0.2) 4 (0.5) 1.00
STROKE n (%) 3 (0.7) 4 (0.5) 0.69
PULMONARY EVENT n (%)      
Cough 7 (1.7) 19 (2.3) 0.67
Dyspnea 15 (3.7) 27 (3.3) 0.74
ENDOCRINE EVENT n (%)      
Hyperthyroidism 56/396 (14.1) 67/801 (8.4) 0.002
Hypothyroidism 14/396 (3.5) 44/801 (5.5) 0.15
CARDIAC EVENT n (%)      
Bradycardia or conduction block
   Any event 8 (2.0) 22 (2.7) 0.56
   Serious event 3 (0.7) 8 (1.0) 1.00
Heart failure or shock
   Any event 4 (1.0) 20 (2.4) 0.12
   Serious event 3 (0.7) 13 (1.6) 0.29
Ventricular arrhythmia 2 (0.5) 6 (0.7) 1.00
NEUROLOGIC EVENT n (%)      
Insomnia or other sleep disorder 6 (1.5) 12 (1.4) 1.00
Memory impairment 0 1 (0.1) 1.00
Peripheral neuropathy 1 (0.2) 0 0.33
Paresthesia 4 (1.0) 11 (1.3) 0.78
Tremor 2 (0.5) 6 (0.7) 1.00
GASTROINTESTINAL OR HEPATIC EVENT      
Diarrhea n (%) 20 (4.9) 59 (7.1) 0.14
Nausea n (%) 14 (3.4) 36 (4.3) 0.54
Abnormality of liver function* n/total n (%) 55/405 (13.6) 100/822 (12.2) 0.52
DERMATOLOGIC EVENT n (%)      
Photosensitivity or skin discoloration 1 (0.2) 6 (0.7) 0.44
OTHER      
Elevation of serum creatinine n (%) 1 (0.2) 20 (2.4) 0.004

  Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.1 * An abnormality of liver function was defined as a level of alanine aminotransferase or aspartate aminotransferase of ≥2X upper limit of the normal range (ULN), an alkaline phosphatase level > 1.5X ULN, a γ-glutamyltransferase level >3X ULN, or a total bilirubin level ≥ 2 mg per deciliter. Patients with no abnormality and with at least one missing measurement of liver function were excluded.

Discontinuation

  • In clinical trials, premature discontinuation due to adverse reactions occurred in1
    • - 11.8% of the MULTAQ-treated patients
    • - 7.7% of the placebo-treated patients
  • Most common reasons for discontinuation of therapy with MULTAQ and placebo1
    • - Gastrointestinal disorders (3.2% vs 1.8%)
    • - QT prolongation (1.5% vs 0.5%)

Adverse events in the ATHENA trial3

EVENT Placebo
(N=2313)
MULTAQ
(N=2291)
P-Value
ANY TEAE n (%) 1603 (69.3) 1649 (72.0) 0.048
Cardiac Events      
Any 221 (9.6) 260 (11.3) 0.048
Bradycardia 28 (1.2) 81 (3.5) <0.001
QT-Interval Prolongation 14 (0.6) 40 (1.7) <0.001
Respiratory Events 337(14.6) 332 (14.5) 0.97
Cough 83 (3.6) 83 (3.6) 1.00
Dyspnea 97 (4.2) 120 (5.2) 0.10
Interstitial lung disease 5 (0.2) 5 (0.2) 1.00
Gastrointestinal Events 508 (22.0) 600 (26.2) <0.001
Diarrhea 144 (6.2) 223 (9.7) <0.001
Nausea 72 (3.1) 122 (5.3) <0.001
Abnormal liver-function test* 14 (0.6) 12 (0.5) 0.84
Endocrine Events 25 (1.1) 25 (1.1) 1.00
Hypothyroidism 6 (0.3) 11 (0.5) 0.23
Hyperthyroidism 7 (0.3) 6 (0.3) 1.00
Neurologic Events 381 (16.5) 373 (16.3) 0.87
Dizziness 152 (6.6) 169 (7.4) 0.30
Headache 87 (3.8) 70 (3.1) 0.19
Skin-related Events 176 (7.6) 237 (10.3) 0.001
Rash 47 (2.0) 77 (3.4) 0.006
Urticaria 9 (0.4) 11 (0.5) 0.66
Serum Creatinine Increase 31 (1.3) 108 (4.7) <0.001
ANY SERIOUS TEAE n (%) 489 (21.1) 456 (19.9) 0.31
Cardiac Events 15 (0.6) 15 (0.7) 1.00
Respiratory Events 45 (1.9) 41 (1.8) 0.74
Gastrointestinal Events 68 (2.9) 81 (3.5) 0.28
Endocrine Events 5 (0.2) 4 (0.2) 1.00
Neurologic Events 27 (1.2) 21 (0.9) 0.47
Skin-related Events 6 (0.3) 7 (0.3) 0.79
Increase in Serum Creatinine 1 (<0.1) 5 (0.2) 0.12
Premature Discontinuation of Study Drug because of an Adverse Event n (%) 187 (8.1) 290 (12.7) <0.001

  Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.1 * Results of liver-function tests were coded with the use of hepatobiliary-investigation high-level group terms in the adverse-event database. No scheduled liver-function tests were performed in this study.

Discontinuation

  • In clinical trials, premature discontinuation due to adverse reactions occurred in1
    • - 11.8% of the MULTAQ-treated patients
    • - 7.7% of the placebo-treated patients
  • Most common reasons for discontinuation of therapy with MULTAQ and placebo1
    • - Gastrointestinal disorders (3.2% vs 1.8%)
    • - QT prolongation (1.5% vs 0.5%)

IMPORTANT SAFETY INFORMATION FOR MULTAQ® (dronedarone)

WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION

MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients.

MULTAQ is contraindicated in patients in atrial fibrillation (AFib) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AFib, MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure.

MULTAQ is also contraindicated in patients:

  • With second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker), bradycardia <50 bpm, QTc Bazett interval ≥500 ms or PR interval >280 ms
  • Who are or may become pregnant (Category X) or nursing. MULTAQ may cause fetal harm when administered to a pregnant woman
  • With concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, ritonavir, or drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine antipsychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics
  • With liver or lung toxicity related to the previous use of amiodarone
  • With severe hepatic impairment
  • With hypersensitivity to the active substance or to any of the excipients

Cardiovascular Death in NYHA Class IV or Decompensated Heart Failure

MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization because it doubles the risk of death.

Cardiovascular Death and Heart Failure in Permanent AFib

MULTAQ doubles the risk of cardiovascular death (largely arrhythmic) and heart failure events in patients with permanent AFib. Patients treated with MULTAQ should undergo monitoring of cardiac rhythm no less often than every 3 months. Cardiovert patients who are in AFib (if clinically indicated) or discontinue MULTAQ. MULTAQ offers no benefit in subjects in permanent AFib.

Increased Risk of Stroke in Permanent AFib

In a placebo-controlled study in patients with permanent AFib, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.

New Onset or Worsening Heart Failure

New onset or worsening of heart failure has been reported during treatment with MULTAQ in the postmarketing setting. In a placebo-controlled study in patients with permanent AFib, increased rates of heart failure were observed in patients with normal left ventricular function and no history of symptomatic heart failure, as well as those with a history of heart failure or left ventricular dysfunction.

Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens and requires hospitalization, discontinue MULTAQ.

Liver Injury

Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the postmarketing setting. Advise patients treated with MULTAQ to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment. It is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue MULTAQ and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart MULTAQ in patients without another explanation for the observed liver injury.

Pulmonary Toxicity

Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the post-marketing setting. Onset of dyspnea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, MULTAQ should be discontinued.

Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics

Hypokalemia and hypomagnesemia may occur with concomitant administration of potassium-depleting diuretics. Potassium levels should be within the normal range prior to administration of MULTAQ and maintained in the normal range during administration of MULTAQ.

QT Interval Prolongation

MULTAQ induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation. If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ.

Renal Impairment and Failure

Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.

Small increases in creatinine levels (about 0.1 mg/dL) following MULTAQ treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion. The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation.

Women of Childbearing Potential

Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices.

Drug-Drug Interactions

  • Treatment with Class I or III antiarrhythmics or drugs that are strong inhibitors of CYP 3A must be stopped before starting MULTAQ (see Contraindications)
  • Patients should be instructed to avoid grapefruit juice beverages while taking MULTAQ
  • Calcium channel blockers with depressant effects and beta-blockers could increase the bradycardia effects of MULTAQ on conduction
  • In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AFib) trials, baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in MULTAQ- treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the MULTAQ vs placebo groups

     

    Digoxin can potentiate the electrophysiologic effects of MULTAQ (such as decreased AV- node conduction). MULTAQ 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
  • Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated with MULTAQ. Monitor INR after initiating MULTAQ in patients taking warfarin
  • Statins: Avoid simvastatin doses greater than 10 mg daily. Follow statin label recommendations for use with CYP 3A and P-gP inhibitors such as MULTAQ

Adverse Reactions

In studies, the most common adverse reactions observed with MULTAQ were diarrhea, nausea, abdominal pain, vomiting, and asthenia.

References: 1. Singh BN, Connolly SJ, Crijns HJGM, et al; for the EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999. 2. MULTAQ® (dronedarone) Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC.

References: 1. MULTAQ® (dronedarone) Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC. 2. Hohnloser SH, Crijns HJGM, van Eickels M, et al; for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678. 3. Singh BN, Connolly SJ, Crijns HJGM, et al; for the EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999. 4. Data on file, ATHENA clinical study report. Sanofi-aventis U.S. LLC.

References: 1. MULTAQ® (dronedarone) Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC. 2. Singh BN, Connolly SJ, Crijns HJGM, et al; for the EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999. 3. Hohnloser SH, Crijns HJGM, van Eickels M, et al; for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.

Reference: 1. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society [published update to January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014;64(21):e1-e76]. Circ. 2019;139:[in press].

Reference: 1. MULTAQ® (dronedarone) Prescribing Information. Bridgewater, NJ: sanofi-aventis U.S. LLC.

*

Back to the top ▲

© 2019 sanofi-aventis U.S. LLC, A SANOFI COMPANY All rights reserved.

Legal Disclaimer | Privacy Policy | Contact SANOFI

This site is intended for use by U.S. healthcare professionals only.

SAUS.DRO.19.03.1825a Last Updated: June 2019

IMPORTANT SAFETY INFORMATION FOR MULTAQ® (dronedarone)

WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION

MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients.

MULTAQ is contraindicated in patients in atrial fibrillation (AFib) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AFib, MULTAQ doubles