Dosage & 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
MULTAQ is contraindicated in patients with:
Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ
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
MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone administered to pregnant rats and rabbits during the period of organogenesis caused multiple visceral (rats) and skeletal malformations (rats and rabbits) when administered at doses equivalent to or lower than the maximum recommended human dose (MRHD)
Animal data
When pregnant rats in embryofetal development studies received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m2basis) during organogenesis (gestational days 6 to 15) fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactyly, syndactyly, and anterior and/or posterior club feet). When pregnant rabbits in embryofetal development studies received dronedarone, at a dose approximately half the MRHD (on a mg/m2basis) during organogenesis (gestational days 6 to 18), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2basis).
Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)
MULTAQ may cause fetal harm when administered to pregnant women
Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ.
Advise female patients of reproductive potential to use effective contraception during treatment with MULTAQ and for 5 days after the final dose.
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Multaq prescribing information
Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. Baseline digoxin therapy was reported in 6/16 dronedarone patients versus 1/16 placebo patients who died of arrhythmia. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone versus placebo groups.
There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 vs 51 for placebo)
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)
- Recently decompensated heart failure requiring hospitalization or Class IV heart failure
- 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 a strong CYP3A inhibitor
- Concomitant use of erythromycin
- Concomitant use of drugs or herbal products that prolong the QT interval and may induce torsade de pointes
- 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
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.
Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF <40%, peripheral arterial occlusive disease, or age >75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.
After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in:
- Mortality: 25 dronedarone versus 13 placebo (HR, 1.94; CI: 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone versus placebo groups.
- Stroke: 23 dronedarone versus 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0[see Warnings and Precautions (5.3)].
- Hospitalizations for heart failure in the dronedarone group: 43 dronedarone versus 24 placebo (HR, 1.81; CI: 1.10 to 2.99).
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)
- Recently decompensated heart failure requiring hospitalization or Class IV heart failure
- 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 a strong CYP3A inhibitor
- Concomitant use of erythromycin
- Concomitant use of drugs or herbal products that prolong the QT interval and may induce torsade de pointes
- 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
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.
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)
ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.
Initially patients were to be ≥70 years old, or <70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or LVEF <0.40). The inclusion criteria were later changed such that patients were to be ≥75 years old, or ≥70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation.
Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs) (69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).
The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.
Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Seventy-one percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).
Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.
Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.
| Placebo | MULTAQ 400 mg BID | ||||
|---|---|---|---|---|---|
| (N=2327) | (N=2301) | HR | 95% CI | p-Value | |
Primary endpoint | |||||
| Cardiovascular hospitalization or death from any cause | 913 (39.2%) | 727 (31.6%) | 0.76 | [0.68–0.83] | <0.0001 |
Components of the endpoint (as first event) | |||||
| 856 (36.8%) | 669 (29.1%) | |||
| 57 (2.4%) | 58 (2.5%) | |||
Secondary endpoints (any time in study) | |||||
| 135 (5.8%) | 115 (5.0%) | 0.86 | [0.67–1.11] | 0.24 |
| 856 (36.8%) | 669 (29.1%) | 0.74 | [0.67–0.82] | <0.0001 |
Components of the cardiovascular hospitalization endpoint (as first event) | |||||
| 456 (19.6%) | 292 (12.7%) | 0.61 | [0.53–0.71] | <0.0001 |
| 400 (17.2%) | 377 (16.4%) | 0.89 | [0.77–1.03] | 0.11 |
The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 3. The event curves separated early and continued to diverge over the 30-month follow-up period.
Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventricular arrhythmia (<1% in both groups).
The reduction in cardiovascular hospitalization or death from any cause was generally consistent in all subgroups based on baseline characteristics or medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure 4).
(a) Determined from Cox regression model
(b) P-value of interaction between baseline characteristics and treatment based on Cox regression model
(c) Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil
In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either MULTAQ 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entry but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common comorbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%). Patients were followed for 12 months.
In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%, with an absolute difference in recurrence rate of about 11% at 12 months.
Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. Baseline digoxin therapy was reported in 6/16 dronedarone patients versus 1/16 placebo patients who died of arrhythmia. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone versus placebo groups.
There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 vs 51 for placebo)
Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF <40%, peripheral arterial occlusive disease, or age >75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo.
After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in:
- Mortality: 25 dronedarone versus 13 placebo (HR, 1.94; CI: 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone versus placebo groups.
- Stroke: 23 dronedarone versus 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0[see Warnings and Precautions (5.3)].
- Hospitalizations for heart failure in the dronedarone group: 43 dronedarone versus 24 placebo (HR, 1.81; CI: 1.10 to 2.99).
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
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)
- Recently decompensated heart failure requiring hospitalization or Class IV heart failure
- 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 a strong CYP3A inhibitor
- Concomitant use of erythromycin
- Concomitant use of drugs or herbal products that prolong the QT interval and may induce torsade de pointes
- 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
Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ
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
MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone administered to pregnant rats and rabbits during the period of organogenesis caused multiple visceral (rats) and skeletal malformations (rats and rabbits) when administered at doses equivalent to or lower than the maximum recommended human dose (MRHD)
Animal data
When pregnant rats in embryofetal development studies received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m2basis) during organogenesis (gestational days 6 to 15) fetuses had increased rates of external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactyly, syndactyly, and anterior and/or posterior club feet). When pregnant rabbits in embryofetal development studies received dronedarone, at a dose approximately half the MRHD (on a mg/m2basis) during organogenesis (gestational days 6 to 18), fetuses had an increased rate of skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m2basis).
Actual animal doses: rat (≥80 mg/kg/day); rabbit (≥20 mg/kg)
MULTAQ may cause fetal harm when administered to pregnant women
Verify that females of reproductive potential are not pregnant prior to initiating MULTAQ.
Advise female patients of reproductive potential to use effective contraception during treatment with MULTAQ and for 5 days after the final dose.
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.
- Lactation: Do not breastfeed (
8.2 LactationRisk SummaryThere are no available data on the presence of dronedarone in human milk, the effects on the breastfed infant, or the effect on milk production. Dronedarone and its metabolites are present in rat milk. During a prenatal and postnatal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in breastfed infants from MULTAQ like the adverse effects in adults, (liver injury, and pulmonary toxicity), advise patients not to breastfeed during treatment with MULTAQ and for 5 days (about 6 half-lives) after the last dose.
MULTAQ is contraindicated in patients with:
- Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored) [see,WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATIONIn patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure, MULTAQ doubles the risk of death[see Clinical Studies (14.3)]. MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure[see Contraindications (4), Warnings and Precautions (5.1)].In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure[see Clinical Studies (14.4)]. MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm[see Contraindications (4), Warnings and Precautions (5.2)].
WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION
See full prescribing information for complete boxed warning.MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients.MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure.]5.2 Cardiovascular Death and Heart Failure in Permanent AFMULTAQ 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.
- Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [see,WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATIONIn patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure, MULTAQ doubles the risk of death[see Clinical Studies (14.3)]. MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure[see Contraindications (4), Warnings and Precautions (5.1)].In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure[see Clinical Studies (14.4)]. MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm[see Contraindications (4), Warnings and Precautions (5.2)].
WARNING: INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION
See full prescribing information for complete boxed warning.MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure. MULTAQ doubles the risk of death in these patients.MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm. In patients with permanent AF, MULTAQ doubles the risk of death, stroke, and hospitalization for heart failure.]5.1 Cardiovascular Death in NYHA Class IV or Decompensated Heart FailureMULTAQ 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.
- 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]
7.2 Effects of Other Drugs on DronedaroneKetoconazole and Other Potent CYP3A InhibitorsConcomitant 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 JuicePatients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased
[see Clinical Pharmacology (12.3)].Rifampin and Other CYP3A InducersAvoid 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 BlockersVerapamil 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)]. - Concomitant use of erythromycin [see]
12.3 PharmacokineticsDronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is increased by meals. Its elimination half-life is 13 to 19 hours.
AbsorptionBecause 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 Cmaxand 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 Cmaxand AUC.
DistributionThe
in vitroplasma 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.MetabolismDronedarone 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/EliminationIn a mass balance study with orally administered dronedarone (14C-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 PopulationsGender
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 InteractionsDronedarone 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 vivothe tubular secretion of creatinine a substrate of the organic cation transporter (OCT2)[see Warnings and Precautions (5.9)].In vitrodronedarone 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 - 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