dronedarone 400 MG Oral Tablet [Multaq]

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 ).

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 )

WARNINGS AND PRECAUTIONS • Determine cardiac rhythm at least once every 3 months. If AF is detected discontinue MULTAQ or cardiovert. ( 5.2 ) • Ensure appropriate antithrombotic therapy prior to and throughout MULTAQ use. ( 5.3 ) • Liver injury: If hepatic injury is suspected, discontinue MULTAQ. ( 5.5 ) • If pulmonary toxicity is confirmed, discontinue treatment. ( 5.6 ) • Hypokalemia and hypomagnesemia: Maintain potassium and magnesium levels within the normal range. ( 5.7 ) • Renal impairment: Monitor renal function periodically. ( 5.9 ) • 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. ( 5.10 ) 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 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. 5.6 Pulmonary Toxicity Cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported in patients treated with MULTAQ in the postmarketing setting [see Adverse Reactions (6.2) ] . 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. 5.7 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. 5.8 QT Interval Prolongation MULTAQ is associated with concentration-dependent QTcF interval prolongation (estimated QTcF increase for 400 mg BID with food is 15 ms) [see Clinical Pharmacology (12.2) ] . If the QTc interval is >500 ms, discontinue MULTAQ [see Contraindications (4) ] . 5.9 Renal Impairment and Failure Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure [see Warnings and Precautions (5.4) ] 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. 5.10 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 [see Use in Specific Populations (8.1 , 8.3) ] .

CONTRAINDICATIONS MULTAQ is contraindicated in patients with: • Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored) [see Boxed Warning , Warnings and Precautions (5.2) ] • Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [see Boxed Warning , Warnings and Precautions (5.1) ] • 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 [see Drug Interactions (7.2) ] • Concomitant use of erythromycin [see Clinical Pharmacology (12.3) ] • 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) ( 4 ) • Bradycardia <50 bpm ( 4 ) • Concomitant use of a strong CYP3A inhibitor ( 4 ) • Concomitant use of erythromycin ( 4 ) • Concomitant use of drugs or herbal products that prolong the QT interval and may induce torsade de pointes ( 4 ) • Liver or lung toxicity related to the previous use of amiodarone ( 4 ) • QTc interval >500 ms or PR interval >280 ms ( 4 ) • Severe hepatic impairment ( 4 ) • Hypersensitivity to the active substance or to any of the excipients ( 4 )

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.