Multaq

1 INDICATIONS AND USAGE MULTAQ ® is indicated to reduce the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF) . MULTAQ is an antiarrhythmic drug indicated to reduce the risk of hospitalization for atrial fibrillation (AF) in patients in sinus rhythm with a history of paroxysmal or persistent AF ( 1 , 14 ).

The 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 . Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ . One tablet of 400 mg twice a day with morning and evening meals

5 WARNINGS AND PRECAUTIONS • Determine cardiac rhythm at least once every 3 months. If AF is detected discontinue MULTAQ or cardiovert. • Ensure appropriate antithrombotic therapy prior to and throughout MULTAQ use. • Liver injury: If hepatic injury is suspected, discontinue MULTAQ. • If pulmonary toxicity is confirmed, discontinue treatment. • Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range. • Renal impairment: Monitor renal function periodically. • Embryofetal Toxicity: Based on animal data, MULTAQ may cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception while using MULTAQ.

5.1Cardiovascular 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.

5.2Cardiovascular 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.

5.3Increased 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 . MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy .

5.4New 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.

5.5Liver 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, 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.

5.6Pulmonary Toxicity Cases of

interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the postmarketing 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.

5.7Hypokalemia 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.

5.8QT Interval Prolongation

MULTAQ is associated with concentration-dependent QTcF interval prolongation (estimated QTcF increase for 400 mg BID with food is 15 ms) . If the QTc interval is >500 ms, discontinue MULTAQ .

5.9Renal 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 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.

5.10Embryofetal Toxicity Based on

animal data, MULTAQ may cause fetal harm when administered to a pregnant woman. Dronedarone caused multiple visceral and skeletal malformations in animal reproduction studies when pregnant rats and rabbits were administered dronedarone at doses equivalent to recommended human doses. Advise pregnant women of the potential risk to the fetus.

Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ. Advise females of reproductive potential to use effective contraception during treatment with MULTAQ and for 5 days (about 6 half-lives) after the final dose .

4 CONTRAINDICATIONS MULTAQ is contraindicated in patients with: • Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored) • Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms • 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 CYP3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir • Concomitant use of erythromycin • Concomitant use of 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 • Liver or lung toxicity related to the previous use of amiodarone • QTc interval >500 ms or PR interval >280 ms • Severe hepatic impairment • Hypersensitivity to the active substance or to any of the excipients • Permanent AF (patients in whom normal sinus rhythm will not or cannot be restored) ( Boxed Warning , 4 ) • Recently decompensated heart failure requiring hospitalization or Class IV heart failure ( Boxed Warning , 4 ) • 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 a strong CYP3A inhibitor • Concomitant use of erythromycin • Concomitant use of drugs or herbal products that prolong the QT interval and may induce torsade de pointes • Liver or lung toxicity related to the previous use of amiodarone • QTc interval >500 ms or PR interval >280 ms • Severe hepatic impairment • Hypersensitivity to the active substance or to any of the excipients

8.1Pregnancy Risk Summary

MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone administered to pregnant rats and rabbits during the period of organogenesis caused multiple visceral (rats) and skeletal malformations (rats and rabbits) when administered at doses equivalent to or lower than the maximum recommended human dose (MRHD) . There are no available data on dronedarone use in pregnant women to evaluate for a drug-associated risk of major birth defects or miscarriage or other adverse maternal or fetal outcomes. Advise pregnant women of the potential risk to a fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Animal data When pregnant rats in embryofetal development studies received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m 2 basis) during organogenesis (gestational days 6 to 15) fetuses had increased rates of 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, ectrodactyly, syndactyly, and anterior and/or posterior club feet). When pregnant rabbits in embryofetal development studies received dronedarone, at a dose approximately half the MRHD (on a mg/m 2 basis) during organogenesis (gestational days 6 to 18), fetuses had an increased rate of 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/m 2 basis). Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)

The following safety concerns are described elsewhere in the label: • New or worsening heart failure • Liver Injury • Pulmonary toxicity • Hypokalemia and hypomagnesemia with potassium-depleting diuretics • QT prolongation Most common adverse reactions (≥2%) are diarrhea, nausea, abdominal pain, vomiting, dyspepsia, bradycardia, skin issues (rashes, pruritus, eczema, dermatitis, dermatitis allergic), and asthenia 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.

6.1Clinical 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% vs 1.8% in the placebo group) and QT prolongation (1.5% vs 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 Placebo Dronedarone 400 mg twice daily (N=2875) (N=3282) Gastrointestinal Diarrhea 6% 9% Nausea 3% 5% Abdominal pain 3% 4% Vomiting 1% 2% Dyspeptic signs and symptoms 1% 2% General Asthenic conditions 5% 7% Cardiac Bradycardia 1% 3% 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 (N=2875) (N=3282) Early increases in creatinine ≥10% 21% 51% (N=2237) (N=2701) QTc prolonged 19% 28% 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 subgroup. In randomized clinical trials of patients with paroxysmal or persistent atrial fibrillation, one case of torsade de pointes was reported in patients treated with MULTAQ (2301 patients) versus no cases of torsade de pointes in patients treated with placebo in the ATHENA study. No cases of torsade de pointes were reported in patients treated with MULTAQ (828 patients) or placebo (409 patients) in the EURIDIS and ADONIS studies .

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval 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. Cardiac: New or worsening heart failure Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely. Hepatic: Liver injury Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis Immune: Anaphylactic reactions including angioedema Vascular: Vasculitis, including leukocytoclastic vasculitis