In patients with paroxysmal or persistent AFib

Efficacy and safety were evaluated in a wide range of patients1,2

Common CV comorbidities in patients in the MULTAQ® pivotal trials

Typical AFib patients*(EURIDIS/ADONIS study: N=1237)1,3

57 % Hypertension


42 % Structural heart disease


22 % Coronary artery disease


17 % CHF (NYHA Class I/II)


AFIB Patients with defineD additional risk factors(Athena study: N=4628)2,3

86 % Hypertension


60 % Structural heart disease


30 % Coronary artery disease


29 % History of CHF (NYHA Class I to III)


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MULTAQ is contraindicated in patients with NYHA Class IV heart failure or symptomatic heart failure with recent decompensation requiring hospitalization.3

* Forms of structural heart disease observed in patients in the EURIDIS/ADONIS trial include valvular disease (16%), nonischemic cardiomyopathy (6%), and hypertrophic cardiomyopathy (3%). Other CV history included implanted pacemaker (7%), rheumatic heart disease (3%), implanted cardioverter/defibrillator (1%), and congenital heart disease (1%).1

Forms of structural heart disease observed in patients in the ATHENA trial include valvular disease (16%) and nonischemic cardiomyopathy (6%). Other CV history included LVEF <45% (12%) and LVEF <35% (4%).3

Common cardiovascular therapies treating patients in the MULTAQ and placebo arms1,2

Typical AFib patients*(EURIDIS/ADONIS study: N=1237)1

70 % Oral anticoagulant


56 % Beta-blocker excluding sotalol


39 % ACE inhibitor


32 % Statin


18 % Calcium channel blocker


AFIB Patients with defineD additional risk factors(Athena study: N=4628)2,3

71 % Beta-blocker


69 % ACE inhibitor or ARB


60 % Oral anticoagulant


39 % Statin


14 % Calcium antagonist


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ATHENA included 196 patients (4.2%) who had undergone ablation for AFib/AFL prior to randomization.4

* Forms of structural heart disease observed in patients in the EURIDIS/ADONIS trial include valvular disease (16%), nonischemic cardiomyopathy (6%), and hypertrophic cardiomyopathy (3%). Other CV history included implanted pacemaker (7%), rheumatic heart disease (3%), implanted cardioverter/defibrillator (1%), and congenital heart disease (1%).1

Forms of structural heart disease observed in patients in the ATHENA trial include valvular disease (16%) and nonischemic cardiomyopathy (6%). Other CV history included LVEF <45% (12%) and LVEF <35% (4%).3

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EURIDIS and ADONIS: Combined baseline characteristics1,*

* Plus–minus values are means ±SD.

Race was determined by the investigators on the basis of hospital records.

The body-mass index was calculated as the weight in kilograms divided by the square of the height in meters. In the European trial, data were missing for 6 subjects in the placebo group and 6 in the MULTAQ group; in the non-European trial, data were missing for 4 subjects in the placebo group and 7 in the MULTAQ group.

§ In the European trial, data were missing for 6 subjects in the placebo group and one in the MULTAQ group; in the non-European trial, data were missing for 2 subjects in the placebo group and 7 in the MULTAQ group.

|| The diagnosis of coronary artery disease was made on the basis of the clinical history and the results of investigational tests.

The diagnosis of congestive heart failure (NYHA Class I and II) was made on clinical grounds. Patients who were classified as having NYHA Class I congestive heart failure had received a diagnosis of the disease but had no symptoms.

ATHENA: Baseline characteristics2,*

* There were no significant differences between the 2 groups for any of the baseline characteristics, with the exception of the proportion of study patients who were women, which was significantly greater in the MULTAQ group (P=0.002).

Complete data on structural heart disease were available for 2281 of the 2301 patients receiving MULTAQ, and for 2304 of the 2327 patients receiving placebo, for a total of 4585 patients.

For left ventricular ejection fraction (LVEF), data were available for 2263 of the 2301 patients receiving MULTAQ, and for 2281 of the 2327 patients receiving placebo, for a total of 4544 patients. The category of LVEF less than 45% included the patients with LVEF of less than 35%.

§ Lone atrial fibrillation was defined as atrial fibrillation in the absence of cardiovascular disease and extracardiac precipitating causes of atrial fibrillation.

img img

Looking for multaq samples?

Impacting the bioavailability of MULTAQ

Efficacy observed using multiple outcome measures

ACC=American College of Cardiology

ACE=angiotensin-converting enzyme

ADONIS=American–Australian–African Trial With Dronedarone in Patients With Atrial Fibrillation or Atrial Flutter Patients for the Maintenance of Sinus Rhythm

AFib=atrial fibrillation

AFL=atrial flutter

AHA=American Heart Association

ARB=angiotensin receptor blocker

ATHENA=A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from any Cause in Patients with Atrial Fibrillation/Atrial Flutter

CHF=congestive heart failure

CV=cardiovascular

EURIDIS=European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm

HF=heart failure

HRS=Heart Rhythm Society

LVEF=left ventricular ejection fraction

NYHA=New York Heart Association

SD=standard deviation

CHARACTERISTIC
Placebo
(n=409)
MULTAQ
(n=828)
SEX—NO. (%)
Female
129 (31.5)
250 (30.2)
Male
280 (68.5)
578 (69.8)
AGE—YR
62.2±11.1
63.5±10.7
RACE—NO. (%)
White
400 (97.8)
880 (96.6)
Black
3 (0.7)
9 (1.1)
Asian
0
6 (0.7)
Other
6 (1.5)
13 (1.6)
BODY-MASS INDEX—NO. (%)
<30
273 (68.4)
538 (66.0)
≥30
126 (31.6)
277 (34.0)
WEIGHT—KG
87.14±17.22
86.25±17.53
CARDIOVASCULAR HISTORY—NO. (%)
Structural heart disease§
159 (39.7)
348 (42.4)
Hypertension
205 (50.1)
497 (60.0)
Coronary artery disease||
75 (18.3)
195 (23.6)
Cardiac valvular disease
61 (14.9)
136 (16.4)
Nonischemic cardiomyopathy
30 (7.3)
50 (6.0)
Implanted pacemaker
20 (4.9)
64 (7.7)
Implanted cardioverter-defibrillator
5 (1.2)
6 (0.7)
Rheumatic heart disease
14 (3.4)
25 (3.0)
Hypertrophic cardiomyopathy
12 (2.9)
23 (2.8)
Congenital heart disease
3 (0.7)
13 (1.6)
LEFT VENTRICULAR EJECTION FRACTION—%
58.5±10.98
58.75±10.77
LEFT ATRIAL ANTEROPOSTERIOR DIAMETER—MM
42.4±6.8
42.6±7.0
CONGESTIVE HEART FAILURE—NO. (%)
Any disease
73 (17.8)
143 (17.3)
NYHA Class I
26 (6.4)
47 (5.7)
NYHA Class II
47 (11.5)
96 (11.6)
SYMPTOMS OF ATRIAL FIBRILLATION IN THE 3 MONTHS BEFORE RANDOMIZATION — NO. (%)
355 (86.8)
726 (87.7)
RECENT CARDIOVERSION (WITHIN 5 DAYS BEFORE RANDOMIZATION) — NO. (%)
121 (29.6)
243 (29.3)
CONCOMITANT CARDIOVASCULAR THERAPY — NO. (%)
Digoxin
95 (23.2)
145 (17.5)
Calcium-channel blocker (rate-lowering)
78 (19.1)
139 (16.8)
Beta-blocker (except sotalol)
238 (58.2)
453 (54.7)
Oral anticoagulant
291 (71.1)
571 (69.0)
Long-term antiplatelet therapy
152 (37.2)
326 (39.4)
Statin
131 (32.0)
263 (31.8)
ACE inhibitor
159 (38.9)
327 (39.5)
PREVIOUS ANTIARRHYTHMIC TREATMENT — NO. (%)
Class IA
40 (9.8)
82 (9.9)
Class IB
0
6 (0.7)
Class IC
108 (26.4)
190 (22.9)
Class II
67 (16.4)
159 (19.2)
Class III
27 (6.6)
86 (10.4)
Class IV
38 (9.3)
72 (8.7)
Amiodarone
126 (30.8)
243 (29.3)
Sotalol
112 (27.4)
214 (25.8)
CHARACTERISTIC
Placebo
(n=2327)
MULTAQ
(n=2301)
AGE
Mean ± SD — yr
71.7±9.0
71.6±8.9
<65 yr — no. (%)
442 (19.0)
431 (18.7)
65 to <75 yr — no. (%)
907 (39.0)
923 (40.1)
≥75 yr — no. (%)
978 (42.0)
947 (41.2)
FEMALE SEX — NO. (%)
1038 (44.6)
1131 (49.2)
ATRIAL FIBRILLATION OR FLUTTER — NO. (%)
586 (25.2)
569 (24.7)
STRUCTURAL HEART DIESEASE — NO. (%)
1402 (60.9)
1330 (58.3)
HYPERTENSION — NO. (%)
1996 (85.8)
1999 (86.9)
CORONARY HEART DISEASE — NO. (%)
737 (31.7)
668 (29.0)
VALVULAR HEART DISEASE — NO. (%)
380 (16.3)
379 (16.5)
NONISCHEMIC CARDIOMYOPATHY — NO. (%)
131 (5.6)
123 (5.3)
HISTORY OF HF, NYHA CLASS II OR III — NO. (%)
515 (22.1)
464 (20.2)
LVEF — NO. (%)
<45%
285 (12.5)
255 (11.3)
<35%
87 (3.8)
92 (4.1)
LONE ATRIAL FIBRILLATION — NO. (%)§
139 (6.0)
140 (6.1)
PACEMAKER — NO. (%)
243 (10.4)
214 (9.3)
MEDICATIONS IN USE AT BASELINE — NO. (%)
Beta-blocker
1641 (70.5)
1628 (70.8)
Calcium antagonists
307 (13.2)
331 (14.4)
Digoxin
308 (13.2)
321 (14.0)
ACE inhibitor or ARB
1602 (68.8)
1614 (70.1)
Statins
914 (39.2)
878 (38.2)
Vitamin K antagonists
1384 (59.5)
1403 (61.0)
Aspirin
1019 (43.8)
1018 (44.2)

INDICATION

MULTAQ is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AFib) in patients in sinus rhythm with a history of paroxysmal or persistent AFib.

IMPORTANT SAFETY INFORMATION

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. 1. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.
  2. 2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2014;64(21):e1-e76.
  3. 3. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.
  4. 4. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.

References:

  1. 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.
  2. 2. Thind M, Crijns HJ, Naccarelli GV, et al. Dronedarone treatment following cardioversion in patients with atrial fibrillation/flutter: a post hoc analysis of the EURIDIS and ADONIS trials. J Cardiovasc Electrophysiol. Published online: February 21, 2020 (doi: 10.1111/jce.14405).

References:

  1. 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.
  2. 2. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.
  3. 3. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.
  4. 4. Vamos M, Calking H, Kowey PR, et al. P1034 Impact of ablation status on the efficacy and safety of dronedarone in patients with atrial fibrillation/flutter: a post hoc analysis of the ATHENA trial. Poster presentation at: European Society of Cardiology Congress 2019; August 31–September 4, 2019; Paris, France.
  5. 5. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2014;64(21):e1-e76.

References:

  1. 1. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.
  2. 2. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.
  3. 3. Pisters R, Hohnloser SH, Connolly SJ, et al; for the ATHENA investigators. Effect of dronedarone on clinical end points in patients with atrial fibrillation and coronary heart disease: insights from the ATHENA trial. Europace. 2014;16(2):174-181.

References:

  1. 1. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.
  2. 2. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.
  3. 3. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.

References:

  1. 1. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.
  2. 2. Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357(10):987-999.
  3. 3. Hohnloser SH, Crijns HJ, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009;360(7):668-678.

References:

  1. 1. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.
  2. 2. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2014;64(21):e1-e76.

References:

  1. 1. MULTAQ [package insert]. Bridgewater, NJ. sanofi-aventis U.S. LLC; 2017.

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MAT-US-2002102 Last Updated: June 2020

IMPORTANT SAFETY INFORMATION

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