Dronedarone - Warnings and Precautions

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.

5.1 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 ] .

MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [see Drug Interactions ] .

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 ] .

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.