Dronedarone

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.

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) [see Clinical Studies (14) ] . 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 ).

2 DOSAGE AND ADMINISTRATION 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 [see Contraindications (4) ] . Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ [see Warnings and Precautions (5.10) , Use in Specific Populations (8.1 , 8.3) ]. One tablet of 400 mg twice a day with morning and evening meals ( 2 )

6 ADVERSE REACTIONS The following safety concerns are described elsewhere in the label: • New or worsening heart failure [see Warnings and Precautions (5.4) ] • Liver Injury [see Warnings and Precautions (5.5) ] • Pulmonary toxicity [see Warnings and Precautions (5.6) ] • Hypokalemia and hypomagnesemia with potassium-depleting diuretics [see Warnings and Precautions (5.7) ] • QT prolongation [see Warnings and Precautions (5.8) ] Most common adverse reactions (≥2%) are diarrhea, nausea, abdominal pain, vomiting, dyspepsia, bradycardia, skin issues (rashes, pruritus, eczema, dermatitis, dermatitis allergic), 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. 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% 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 (2327) 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 [see Clinical Studies (14) ] . 6.2 Postmarketing 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 [see Warnings and Precautions (5.4) ] Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely. Hepatic: Liver injury [see Warnings and Precautions (5.5) ] Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis [see Warnings and Precautions (5.6) ] Immune: Anaphylactic reactions including angioedema Vascular: Vasculitis, including leukocytoclastic vasculitis

7 DRUG INTERACTIONS Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A and CYP2D6 and has potentially important pharmacodynamic interactions ( 7 ) • Class I or III antiarrhythmics: Contraindicated. ( 4 , 7.1 ) • Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor digoxin levels. ( 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 ) • CYP3A inducers: Avoid concomitant use. ( 7.2 ) • Grapefruit juice: Avoid concomitant use. ( 7.2 ) • Statins: Avoid simvastatin doses greater than 10 mg daily. Follow label recommendations for concomitant use of other statins with a CYP3A and P-gp inhibitor like dronedarone. ( 7.3 ) • CYP3A 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 ) 7.1 Pharmacodynamic Interactions Drugs Prolonging the QT Interval (Inducing Torsade de Pointes) Coadministration of drugs prolonging the QT interval (such as certain phenothiazines, tricyclic antidepressants, certain macrolide antibiotics, and Class I and III antiarrhythmics) is contraindicated because of the potential risk of torsade de pointes–type ventricular tachycardia [see Contraindications (4) , Clinical Pharmacology (12.3) ] . Digoxin In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone versus placebo groups [see Clinical Studies (14.3) ] . Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin [see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ] . Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity . Calcium Channel Blockers Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone's effects on conduction. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ] . Beta-Blockers In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers. Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability [see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ] . 7.2 Effects of Other Drugs on Dronedarone Ketoconazole and Other Potent CYP3A Inhibitors Concomitant use of ketoconazole as well as other potent CYP3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased [see Contraindications (4) , Clinical Pharmacology (12.3) ] . Grapefruit Juice Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased [see Clinical Pharmacology (12.3) ] . Rifampin and Other CYP3A Inducers Avoid rifampin or other CYP3A inducers such as phenobarbital, carbamazepine, phenytoin, and St. John's wort because they decrease exposure to dronedarone significantly [see Clinical Pharmacology (12.3) ] . Calcium Channel Blockers Verapamil and diltiazem are moderate CYP3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3) , Clinical Pharmacology (12.3) ] . 7.3 Effects of Dronedarone on Other Drugs Simvastatin Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin [see Clinical Pharmacology (12.3) ] . Other Statins Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP3A and P-gp inhibitors such as dronedarone. Calcium Channel Blockers Dronedarone increased the exposure of calcium channel blockers (verapamil, diltiazem or nifedipine). Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Sirolimus, Tacrolimus, and Other CYP3A Substrates with Narrow Therapeutic Range Dronedarone can increase plasma concentrations of tacrolimus, sir