5.1 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.

5.2 Cardiovascular Death and Heart Failure in Permanent AF

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

5.3 Increased Risk of Stroke in Permanent AF

In a placebo-controlled study in patients with permanent atrial fibrillation, dronedarone was associated with an increased risk of stroke, particularly in the first two weeks of therapy [see Clinical Studies (14.4)]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [see Drug interactions (7.3)].

5.4 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 AF 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.

5.5 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, but 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.

5.6 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.

5.7 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, discontinue MULTAQ [see Contraindications (4)].

5.8 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.

5.9 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. [see Use in Specific Populations (8.1)].

6.1 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.

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.

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.

6.2 Postmarketing Experience

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.

7.1 Pharmacodynamic Interactions

7.2 Effects of Other Drugs on Dronedarone

7.3 Effects of Dronedarone on Other Drugs

8.1 Pregnancy

8.3 Nursing Mothers

It is not known whether MULTAQ is excreted in human milk. Dronedarone and its metabolites are excreted in rat milk. During a pre- and post-natal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MULTAQ, discontinue nursing or discontinue the drug [see Contraindications (4)].

8.4 Pediatric Use

Safety and efficacy in children below the age of 18 years have not been established.

8.5 Geriatric Use

More than 4500 patients with AF or AFL aged 65 years or above were included in the MULTAQ clinical program (of whom more than 2000 patients were 75 years or older). Efficacy and safety were similar in elderly and younger patients.

8.6 Renal Impairment

Patients with renal impairment were included in clinical studies. Because renal excretion of dronedarone is minimal [see Clinical Pharmacology (12.3)], no dosing alteration is needed.

8.7 Hepatic Impairment

Dronedarone is extensively metabolized by the liver. There is little clinical experience with moderate hepatic impairment and none with severe impairment. No dosage adjustment is recommended for moderate hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

The mechanism of action of dronedarone is unknown. Dronedarone has antiarrhythmic properties belonging to all four Vaughan-Williams classes, but the contribution of each of these activities to the clinical effect is unknown.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

Dronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is increased by meals. Its elimination half life is 13–19 hours.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

In studies in which dronedarone was administered to rats and mice for up to 2 years at doses of up to 70 mg/kg/day and 300 mg/kg/day, respectively, there was an increased incidence of histiocytic sarcomas in dronedarone-treated male mice (300 mg/kg/day or 5× the maximum recommended human dose based on AUC comparisons), mammary adenocarcinomas in dronedarone-treated female mice (300 mg/kg/day or 8× MRHD based on AUC comparisons) and hemangiomas in dronedarone-treated male rats (70 mg/kg/day or 5× MRHD based on AUC comparisons).

Dronedarone did not demonstrate genotoxic potential in the in vivo mouse micronucleus test, the Ames bacterial mutation assay, the unscheduled DNA synthesis assay, or an in vitro chromosomal aberration assay in human lymphocytes. S-9 processed dronedarone, however, was positive in a V79 transfected Chinese hamster V79 assay.

In fertility studies conducted with female rats, dronedarone given prior to breeding and implantation caused an increase in irregular estrus cycles and cessation of cycling at doses ≥10mg/kg (equivalent to 0.12× the MRHD on a mg/m2 basis).

Corpora lutea, implantations and live fetuses were decreased at 100 mg/kg (equivalent to 1.2× the MRHD on a mg/m2 basis). There were no reported effects on mating behavior or fertility of male rats at doses of up to 100 mg/kg/day.

13.3 Developmental Toxicity

Dronedarone was teratogenic in rats given oral doses ≥80 mg/kg/day (a dose equivalent to the maximum recommended human dose [MHRD] on a mg/m2 basis), with fetuses showing external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). In rabbits, dronedarone caused an increase in skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2 basis).

14.1 ATHENA

ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.

Initially patients were to be ≥70 years old, or <70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or LVEF<0.40). The inclusion criteria were later changed such that patients were to be ≥75 years old, or ≥70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation.

Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs)(69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).

The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.

Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).

Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.

Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.

The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 1. The event curves separated early and continued to diverge over the 30 month follow-up period.

Figure 1: Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from any Cause

Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (<1% in both groups).

The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure 2).

Figure 2: Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from any Cause.

a Determined from Cox regression model
b P-value of interaction between baseline characteristics and treatment based on Cox regression model
c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil

14.2 EURIDIS and ADONIS

In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either MULTAQ 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months.

In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.

14.3 ANDROMEDA

Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo) [see Boxed Warning and Contraindications (4)].

14.4 PALLAS

Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF <40%, peripheral arterial occlusive disease, or age >75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.

After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months days for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in

• Mortality: 25 dronedarone vs. 13 placebo (HR, 1.94; CI, 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin.
• Stroke: 23 dronedarone vs. 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs. 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0.[see Warning and Precaution (5.3)]
• Hospitalizations for heart failure in the dronedarone group: 43 dronedarone vs. 24 placebo (HR, 1.81; CI: 1.10 to 2.99).

Store at 25°C (77°F): excursions permitted to 15–30°C (59–86°F), [see USP controlled room temperature].

17.1 Information for Patients

[See Medication Guide (17.2)]

MULTAQ should be administered with a meal. Warn patients not to take MULTAQ with grapefruit juice.

If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.

Advise patients to consult a physician if they develop signs or symptoms of heart failure such as acute weight gain, dependent edema, or increasing shortness of breath.

Advise patients to immediately report any symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) to their physician.

Advise patients to inform their physician of any history of heart failure, rhythm disturbance other than atrial fibrillation or flutter or predisposing conditions such as uncorrected hypokalemia.

MULTAQ may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.

17.2 Medication Guide

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