Dronedarone HCl is a benzofuran derivative with the following chemical name: N -{2-butyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl} methanesulfonamide, hydrochloride. Dronedarone HCl is a white fine powder that is practically insoluble in water and freely soluble in methylene chloride and methanol. Its empirical formula is C 31 H 44 N 2 O 5 S, HCl with a relative molecular mass of 593.2. Its structural formula is: MULTAQ is provided as tablets for oral administration. Each tablet of MULTAQ contains 400 mg of dronedarone (expressed as base). The inactive ingredients are: Core of the tablets: Colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, poloxamer 407, starch. Coating/polishing of the tablets: Carnauba wax, hypromellose, polyethylene glycol 6000, titanium dioxide. Chemical Structure

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 ).

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. 400 mg film-coated tablets

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

• 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. 5.1 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

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

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 . 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 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

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, 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

Pulmonary 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

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

QT 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

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 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

Embryofetal 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 .

Dronedarone is metabolized by CYP3A and is a moderate inhibitor of CYP3A and CYP2D6 and has potentially important pharmacodynamic interactions • Class I or III antiarrhythmics: Contraindicated. • Digoxin: Consider discontinuation or halve dose of digoxin before treatment and monitor digoxin levels. • 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. • CYP3A inducers: Avoid concomitant use. • Grapefruit juice: Avoid concomitant use. • 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. • 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. • Warfarin: Monitor INR after initiating dronedarone in patients taking warfarin

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 . 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 . Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone 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 . 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 . 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

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 . Grapefruit Juice Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased . 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 . 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

Effects of Dronedarone on Other Drugs Simvastatin Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin . 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 . Sirolimus, Tacrolimus, and Other CYP3A Substrates with Narrow Therapeutic Range Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately. Beta-Blockers and Other CYP2D6 Substrates Dronedarone increased the exposure of propranolol and metoprolol. Give low doses of beta-blockers initially, and increase only after ECG verification of good tolerability. Other CYP2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon coadministration with dronedarone . P-glycoprotein Substrates Digoxin Dronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity . Dabigatran Dronedarone increases dabigatran plasma exposures by inhibiting the P-gp transporter . In patients with moderate renal impairment (CrCL 30–50 mL/min), reduce the dose of dabigatran to 75 mg twice daily when concomitantly administered with dronedarone. In patients with severe renal impairment (CrCL 15–30 mL/min), concomitant use of dronedarone with dabigatran should be avoided. Warfarin When coadministered with dronedarone exposure to S-warfarin was slightly higher than when warfarin was administered alone. There were no clinically significant increases in INR . More patients experienced clinically significant INR elevations (≥5) usually within 1 week after starting dronedarone versus placebo in patients taking oral anticoagulants in ATHENA. However, no excess risk of bleeding was observed in the dronedarone group. Postmarketing cases of increased INR with or without bleeding events have been reported in warfarin-treated patients initiated on dronedarone. Monitor INR after initiating dronedarone in patients taking warfarin.