These highlights do not include all the information needed to use MULTAQ safely and effectively. See full prescribing information for MULTAQ.
MULTAQ (dronedarone) Tablets
Initial U.S. Approval: 2009
WARNING: HEART FAILURE
MULTAQ is contraindicated in patients with NYHA Class IV heart failure or NYHA Class II – III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic (4).
In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone (14.3).
RECENT MAJOR CHANGES
•Warnings and Precautions, Liver Injury (5.2)
02/2011
•Warnings and Precautions, Increase in Creatinine after Treatment Initiation (5.5)
08/2011
INDICATIONS AND USAGE
MULTAQ is an antiarrhythmic drug indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted (1, 14).
DOSAGE AND ADMINISTRATION
One tablet of 400 mg twice a day with morning and evening meals (2)
DOSAGE FORMS AND STRENGTHS
400 mg film-coated tablets (3)
CONTRAINDICATIONS
Class IV heart failure or symptomatic heart failure with a recent decompensation (Boxed Warning, 4)
Second- or third- degree atrioventicular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker) (4)
Bradycardia <50 bpm (4)
Concomitant use of a strong CYP3A inhibitor (4)
Concomitant use of drugs or herbal products that prolong the QT interval and may induce Torsade de Pointes (4)
Severe hepatic impairment (4)
QTc Bazett interval ≥500 ms (4)
Pregnancy (4, 8.1)
Nursing mothers (4, 8.3)
WARNINGS AND PRECAUTIONS
Heart failure: If heart failure develops or worsens, consider the suspension or discontinuation of MULTAQ (5.1)
Liver injury: if hepatic injury is suspected, discontinue MULTAQ (5.2)
Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range (5.3)
QT prolongation: Stop MULTAQ if QTc Bazett ≥500ms (5.4)
Increase in creatinine: Monitor serum creatinine periodically (5.5)
Teratogen: Women of childbearing potential should use effective contraception while using MULTAQ (5.6)
ADVERSE REACTIONS
Most common adverse reactions (≥2%) are diarrhea, nausea, abdominal pain, vomiting, and asthenia (6)
To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
DRUG INTERACTIONS
Dronedarone is metabolized by CYP 3A and is a moderate inhibitor of
CYP 3A and CYP 2D6 and has potentially important pharmacodynamic interactions (7)
Antiarrhythmics: Avoid concomitant use (4, 7.1)
Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor (7.1, 7.3)
Calcium channel blockers (CCB): Initiate CCB with low dose and increase after ECG verification of tolerability (7.1,7.2, 7.3)
Beta-blockers: May provoke excessive bradycardia, Initiate with low dose and increase after ECG verification of tolerability (7.1, 7.3)
CYP 3A inducers: Avoid concomitant use (7.2)
Grapefruit juice: Avoid concomitant use (7.2)
Statins: Follow label recommendations for concomitant use of certain statins with a CYP 3A and P-gP inhibitor like dronedarone (7.3)
CYP 3A substrates with a narrow therapeutic index (e.g., sirolimus and tacrolimus): Monitor and adjust dosage of concomitant drug as needed when used with MULTAQ (7.3)
Warfarin: Monitor INR after initiating dronedarone in patients taking warfarin. (7.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide
Revised: 08/2011
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
* Sections or subsections omitted from the full prescribing information are not listed
WARNING: HEART FAILURE
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Patients with New or Worsening Heart Failure during Treatment
5.2 Liver Injury
5.3 Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics
5.4 QT Interval Prolongation
5.5 Increase in Creatinine after Treatment Initiation
5.6 Women of Childbearing Potential
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Pharmacodynamic Interactions
7.2 Effects of Other Drugs on Dronedarone
7.3 Effects of Dronedarone on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.3Developmental Toxicity
14 CLINICAL STUDIES
14.1 ATHENA Study
14.2 EURIDIS and ADONIS Studies
14.3 ANDROMEDA Study (Increased Mortality in Patients with Severe or Recently Decompensated Heart Failure)
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
17.1 Information for Patients
17.2 Medication Guide
FULL PRESCRIBING INFORMATION
WARNING: HEART FAILURE
MULTAQ is contraindicated in patients with NYHA Class IV heart failure, or NYHA Class II – III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic [see Contraindications (4)].
In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone [see Clinical Studies (14.3)].
1 INDICATIONS AND USAGE
MULTAQ® is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted [see Clinical Studies (14)].
2 DOSAGE AND ADMINISTRATION
The only recommended dosage of MULTAQ is 400 mg twice daily in adults. MULTAQ should be taken as one tablet with the morning meal and one tablet with the evening meal.
Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ [see Contraindications (4)].
3 DOSAGE FORMS AND STRENGTHS
MULTAQ 400 mg tablets are provided as white film-coated tablets for oral administration, oblong-shaped, engraved with a double wave marking on one side and "4142" code on the other side.
4 CONTRAINDICATIONS
MULTAQ is contraindicated in patients with:
NYHA Class IV heart failure or NYHA Class II – III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic [see Boxed Warning and Clinical Studies (14.3)]
Second- or third-degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker)
Bradycardia <50 bpm
Concomitant use of strong CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see Drug Interactions (7.2)]
Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics
QTc Bazett interval ≥500 ms or PR interval >280 ms
Severe hepatic impairment
Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].
Nursing mothers [see Use in Specific Populations (8.3)]
5 WARNINGS AND PRECAUTIONS
5.1 Patients with New or Worsening Heart Failure during Treatment
Postmarketing cases of new onset and worsening heart failure have been reported during treatment with Multaq. 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, consider the suspension or discontinuation of MULTAQ.
5.2 Liver Injury
Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the post-marketing 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.
5.3 Hypokalemia and Hypomagnesemia with Potassium-Depleting Diuretics
Hypokalemia or 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.
5.4 QT Interval Prolongation
Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see Clinical Pharmacology (12.2) and Clinical Studies (14.1)]. If the QTc Bazett interval is ≥500 ms, MULTAQ should be stopped [see Contraindications (4)].
5.5 Increase in Creatinine after Treatment Initiation
Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone 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.
Larger increases in creatinine after dronedarone initiation have been reported in the postmarketing setting. Some cases also reported increases in blood urea nitrogen. In most cases, these effects appear to be reversible upon drug discontinuation. Monitor renal function periodically.
5.6 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. Women of childbearing potential should be counseled regarding appropriate contraceptive choices taking into consideration their underlying medical conditions and lifestyle preferences [see Use in Specific Populations (8.1)].
6 ADVERSE REACTIONS
The following safety concerns are described elsewhere in the label:
New or worsening heart failure [see Warnings and Precautions (5.1)]
Liver Injury [see Warnings and Precautions (5.2)]
Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see Warnings and Precautions (5.3)]
QT prolongation [see Warnings and Precautions (5.4)]
6.1 Clinical Trials Experience
The safety eva luation 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
