Dronedarone

5 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) ] .

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, 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 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . 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 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] . Dabigatran Dronedarone increases dabigatran plasma exposures by inhibiting the P-gp transporter [see Clinical Pharmacology (12.3) ] . 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 [see Clinical Pharmacology (12.3) ] . 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.

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.

12.2 Pharmacodynamics Electrophysiological Effects The effect of dronedarone on 12-lead ECG parameters was investigated in healthy subjects following repeated oral doses up to 1600 mg twice daily for 10 days. Concentration-dependent increases in QTcF and PR were observed and the estimated increases for 400 mg BID with food are 15 and 12 ms, respectively. The contribution of dronedarone and the N-debutyl metabolite to observed changes is unknown. DAFNE Study DAFNE was a dose-response study in patients with recurrent AF, evaluating the effect of dronedarone in comparison with placebo in maintaining sinus rhythm. The doses of dronedarone in this study were 400, 600, and 800 mg twice a day. In this small study, doses above 400 mg were not more effective and were less well tolerated.

12.3 Pharmacokinetics Dronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is increased by meals. Its elimination half-life is 13 to 19 hours. Absorption Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady-state C max and exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a doubling in dose results in approximately 2.5 to 3.0-fold the C max and AUC. Distribution The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is >98% and not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state is about 1400 L. Metabolism Dronedarone is extensively metabolized, mainly by CYP3A. The initial metabolic pathway includes N-debutylation to form the active N-debutyl metabolite, oxidative deamination to form the inactive propanoic acid metabolite, and direct oxidation. The metabolites undergo further metabolism to yield over 30 uncharacterized metabolites. Monoamine oxidases contribute partially to the metabolism of the active metabolite of dronedarone. Excretion/Elimination In a mass balance study with orally administered dronedarone ( 14 C-labeled) approximately 6% of the labeled dose was excreted in urine, mainly as metabolites (no unchanged compound excreted in urine), and 84% was excreted in feces, mainly as metabolites. Dronedarone and its N-debutyl active metabolite accounted for less than 15% of the resultant radioactivity in the plasma. After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The elimination half-life of dronedarone ranges from 13 to 19 hours. Special Populations Gender Dronedarone exposures are on average 30% higher in females than in males. Race Pharmacokinetic differences related to race were not formally assessed. However, based on a cross study comparison, following single dose administration (400 mg), Asian males (Japanese) have about twice the exposure than Caucasian males. The pharmacokinetics of dronedarone in other races has not been assessed. Elderly Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and over and 34% were 75 and over. In patients aged 65 years old and above, dronedarone exposures are 23% higher than in patients less than 65 years old [see Use in Specific Populations (8.5) ] . Hepatic impairment In subjects with moderate hepatic impairment, the mean dronedarone exposure increased by 30% relative to subjects with normal hepatic function and the mean exposure of the N-debutyl metabolite decreased by about 50%. Pharmacokinetic data were significantly more variable in subjects with moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed [see Contraindications (4) ] . Renal impairment Consistent with the low renal excretion of dronedarone, no pharmacokinetic difference was observed in subjects with mild or moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6) ] . No pharmacokinetic difference was observed in patients with mild to severe renal impairment in comparison with patients with normal renal function. Drug Interactions Dronedarone is metabolized primarily by CYP3A and is a moderate inhibitor of CYP3A and CYP2D6. Dronedarone has no significant potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2C8 and CYP2B6. It has the potential to inhibit P-glycoprotein (P-gp) transport. Dronedarone inhibits in vivo the tubular secretion of creatinine a substrate of the organic cation transporter (OCT2) [see Warnings and Precautions (5.9) ] . In vitro dronedarone and the metabolites SR35021 and SR90154 show no significant potential to inhibit the organic anion transporters OAT1 and OAT3 or the organic cation transporter OCT1. However, in vitro data indicate that SR90154 is likely to inhibit the organic anion transporting polypeptides (OATP1B1, OATP1B3) in vivo . Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of coadministered drugs on dronedarone) and Figure 2 (impact of dronedarone on coadministered drugs). Figure 1: The Impact of Coadministered Drugs on the Pharmacokinetics of Dronedarone and Recommendations for Dronedarone Coadministration or Dose Adjustment Figure 2: The Impact of Dronedarone on Coadministered Drugs and Recommendations for Dose Adjustment of Coadministered Drug Figure 1 Figure 2

Dronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is increased by meals. Its elimination half-life is 13 to 19 hours. Absorption Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady-state C max and exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a doubling in dose results in approximately 2.5 to 3.0-fold the C max and AUC. Distribution The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is >98% and not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state is about 1400 L. Metabolism Dronedarone is extensively metabolized, mainly by CYP3A. The initial metabolic pathway includes N-debutylation to form the active N-debutyl metabolite, oxidative deamination to form the inactive propanoic acid metabolite, and direct oxidation. The metabolites undergo further metabolism to yield over 30 uncharacterized metabolites. Monoamine oxidases contribute partially to the metabolism of the active metabolite of dronedarone. Excretion/Elimination In a mass balance study with orally administered dronedarone ( 14 C-labeled) approximately 6% of the labeled dose was excreted in urine, mainly as metabolites (no unchanged compound excreted in urine), and 84% was excreted in feces, mainly as metabolites. Dronedarone and its N-debutyl active metabolite accounted for less than 15% of the resultant radioactivity in the plasma. After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The elimination half-life of dronedarone ranges from 13 to 19 hours. Special Populations Gender Dronedarone exposures are on average 30% higher in females than in males. Race Pharmacokinetic differences related to race were not formally assessed. However, based on a cross study comparison, following single dose administration (400 mg), Asian males (Japanese) have about twice the exposure than Caucasian males. The pharmacokinetics of dronedarone in other races has not been assessed. Elderly Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and over and 34% were 75 and over. In patients aged 65 years old and above, dronedarone exposures are 23% higher than in patients less than 65 years old [see Use in Specific Populations (8.5) ] . Hepatic impairment In subjects with moderate hepatic impairment, the mean dronedarone exposure increased by 30% relative to subjects with normal hepatic function and the mean exposure of the N-debutyl metabolite decreased by about 50%. Pharmacokinetic data were significantly more variable in subjects with moderate hepatic impairment. The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed [see Contraindications (4) ] . Renal impairment Consistent with the low renal excretion of dronedarone, no pharmacokinetic difference was observed in subjects with mild or moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations (8.6) ] . No pharmacokinetic difference was observed in patients with mild to severe renal impairment in comparison with patients with normal renal function. Drug Interactions Dronedarone is metabolized primarily by CYP3A and is a moderate inhibitor of CYP3A and CYP2D6. Dronedarone has no significant potential to inhibit CYP1A2, CYP2C9, CYP2C19, CYP2C8 and CYP2B6. It has the potential to inhibit P-glycoprotein (P-gp) transport. Dronedarone inhibits in vivo the tubular secretion of creatinine a substrate of the organic cation transporter (OCT2) [see Warnings and Precautions (5.9) ] . In vitro dronedarone and the metabolites SR35021 and SR90154 show no significant potential to inhibit the organic anion transporters OAT1 and OAT3 or the organic cation transporter OCT1. However, in vitro data indicate that SR90154 is likely to inhibit the organic anion transporting polypeptides (OATP1B1, OATP1B3) in vivo . Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of coadministered drugs on dronedarone) and Figure 2 (impact of dronedarone on coadministered drugs). Figure 1: The Impact of Coadministered Drugs on the Pharmacokinetics of Dronedarone and Recommendations for Dronedarone Coadministration or Dose Adjustment Figure 2: The Impact of Dronedarone on Coadministered Drugs and Recommendations for Dose Adjustment of Coadministered Drug Figure 1 Figure 2