Multaq (Dronedarone Tablets)
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Multaq (Dronedarone Tablets)

MULTAQ
(dronedarone) Tablets

WARNING

INCREASED RISK OF DEATH, STROKE AND HEART FAILURE IN PATIENTS WITH DECOMPENSATED HEART FAILURE OR PERMANENT ATRIAL FIBRILLATION

In patients with symptomatic heart failure and recent decompensation requiring hospitalization or NYHA Class IV heart failure; MULTAQ doubles the risk of death. MULTAQ is contraindicated in patients with symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV heart failure.

In patients with permanent atrial fibrillation, MULTAQ doubles the risk of death, stroke and hospitalization for heart failure. MULTAQ is contraindicated in patients in atrial fibrillation (AF) who will not or cannot be cardioverted into normal sinus rhythm.

DRUG DESCRIPTION

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 C31H44N2O5 S, HCl with a relative molecular mass of 593.2. Its structural formula is:

MULTAQ (dronedarone) Structural Formula Illustration

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-hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate. Coating / polishing of the tablets-hypromellose, polyethylene glycol 6000, titanium dioxide, carnauba wax.

What are the possible side effects of dronedarone (Multaq)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • severe dizziness, fainting, fast or pounding heartbeats;
  • slow heart rate, feeling like you might pass out;
  • a new or a worsening irregular heartbeat pattern;
  • feeling short of breath, even with mild exertion, swelling in your ankles or feet, rapid weight gain;
  • wheezing, cough, chest pain, trouble breathing, coughing...

Read All Potential Side Effects and See Pictures of Multaq »

What are the precautions when taking dronedarone tablets (Multaq)?

See also Warning section.

Before taking dronedarone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, certain types of irregular heartbeat (sick sinus syndrome, second- or third-degree atrioventricular block), serious side effects (such as liver/lung disease) from taking the medication amiodarone.

Dronedarone may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat...

Read All Potential Precautions of Multaq »

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

INDICATIONS

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].

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].

HOW SUPPLIED

Dosage Forms And Strengths

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.

Storage And Handling

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 in:

Bottles of 60 tablets, NDC 0024-4142-60
Bottles of 180 tablets, NDC 0024-4142-18
Bottles of 500 tablets NDC 0024-4142-50
Box of 10 blisters (10 tablets per blister) NDC 0024-4142-10

Store at 25°C (77°F): excursions permitted to 15-30°C (59-86°F), [see USP controlled room temperature].

Issued September 2012 Manufactured by Sanofi Winthrop Industrie 1, rue de la Vierge 33440 Ambares, France. Revised: 09/2012

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

SIDE EFFECTS

The following safety concerns are described elsewhere in the label:

Clinical Trials Experience

The safety evaluation of dronedarone 400 mg twice daily in patients with AF or AFL is based on 5 placebo controlled studies, ATHENA, EURIDIS, ADONIS, ERATO and DAFNE. In these studies, a total of 6285 patients were randomized and treated, 3282 patients with MULTAQ 400 mg twice daily, and 2875 with placebo. The mean exposure across studies was 12 months. In ATHENA, the maximum follow-up was 30 months.

In clinical trials, premature discontinuation because of adverse reactions occurred in 11.8% of the dronedarone-treated patients and in 7.7% of the placebo-treated group. The most common reasons for discontinuation of therapy with MULTAQ were gastrointestinal disorders (3.2 % versus 1.8% in the placebo group) and QT prolongation (1.5% versus 0.5% in the placebo group).

The most frequent adverse reactions observed with MULTAQ 400 mg twice daily in the 5 studies were diarrhea, nausea, abdominal pain, vomiting, and asthenia.

Table 1 displays adverse reactions more common with dronedarone 400 mg twice daily than with placebo in AF or AFL patients, presented by system organ class and by decreasing order of frequency. Adverse laboratory and ECG effects are presented separately in Table 2.

Table 1: Adverse Drug Reactions that Occurred in at Least 1% of Patients and Were More Frequent than Placebo

  Placebo (N=2875) Dronedarone 400 mg twice daily (N=3282)
Gastrointestinal
Diarrhea 6% 9%
Nausea 3% 5%
Abdominal pain 3% 4%
Vomiting 1% 2%
Dyspeptic signs and symptoms 1% 2%
General
Asthenic conditions 5% 7%
Cardiac
Bradycardia 1% 3%
Skin and subcutaneous tissue
Including rashes (generalized, macular, maculo-papular, erythematous), pruritus, eczema, dermatitis, dermatitis allergic 3% 5%

Photosensitivity reaction and dysgeusia have also been reported at an incidence less than 1% in patients treated with MULTAQ.

The following laboratory data/ECG parameters were reported with MULTAQ 400 mg twice daily.

Table 2: Laboratory data/ECG parameters not necessarily reported as adverse events

  Placebo
MULTAQ 400 mg twice daily
  (N=2875) (N=3282)
Early increases in creatinine ?10% 21% 51%
  (N=2237) (N=2701)
QTc prolonged 19% 28%

Assessment of demographic factors such as gender or age on the incidence of treatment- emergent adverse events did not suggest an excess of adverse events in any particular sub-group.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of MULTAQ. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac: New or worsening heart failure [see WARNINGS AND PRECAUTIONS]

Hepatic: Liver Injury [see WARNINGS AND PRECAUTIONS]

Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis [see WARNINGS AND PRECAUTIONS]

Immune: Anaphylactic reactions including angioedema

Vascular: Vasculitis, including leukocytoclastic vasculitis

Read the Multaq (dronedarone tablets) Side Effects Center for a complete guide to possible side effects »

DRUG INTERACTIONS

Pharmacodynamic Interactions

Drugs prolonging the QT interval (inducing Torsade de Pointes)

Co-administration 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, CLINICAL PHARMACOLOGY].

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 vs. placebo groups. [See Clinical Trials]).

Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin [see CLINICAL PHARMACOLOGY].

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 CLINICAL PHARMACOLOGY].

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 CLINICAL PHARMACOLOGY].

Effects of Other Drugs on Dronedarone

Ketoconazole and other potent CYP 3A inhibitors

Concomitant use of ketoconazole as well as other potent CYP 3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased [see CONTRAINDICATIONS, CLINICAL PHARMACOLOGY].

Grapefruit juice

Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased [see CLINICAL PHARMACOLOGY].

Rifampin and other CYP 3A inducers

Avoid rifampin or other CYP 3A inducers such as phenobarbital, carbamazepine, phenytoin, and St John's wort because they decrease exposure to dronedarone significantly [see CLINICAL PHARMACOLOGY].

Calcium channel blockers

Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure. Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see CLINICAL PHARMACOLOGY].

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].

Other statins

Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A 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 CLINICAL PHARMACOLOGY].

Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range

Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.

Beta-blockers and other CYP 2D6 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 CYP 2D6 substrates, including other beta-blockers, tricyclic antidepressants, and selective serotonin reuptake inhibitors (SSRIs) may have increased exposure upon co-administration with dronedarone [see CLINICAL PHARMACOLOGY].

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 CLINICAL PHARMACOLOGY].

Dabigatran

Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone.

Other P-gp substrates are expected to have increased exposure when co-administered with dronedarone.

Warfarin

When co-administered 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].

More patients experienced clinically significant INR elevations ( ≥ 5) usually within 1 week after starting dronedarone vs. 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.

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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 [see Clinical Studies]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [see DRUG INTERACTIONS].

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 post-marketing 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.

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

Dronedarone induces a moderate (average of about 10 ms but much greater effects have been observed) QTc (Bazett) prolongation [see CLINICAL PHARMACOLOGY and Clinical Studies]. If the QTc Bazett interval is ≥ 500 ms, discontinue MULTAQ [see CONTRAINDICATIONS].

Increase in Creatinine after Treatment Initiation

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. Larger increases in creatinine after dronedarone initiation have been reported in the postmarketing setting. Some cases also reported increases in blood urea nitrogen. In most cases, these effects appear to be reversible upon drug discontinuation. Monitor renal function periodically.

Women of Childbearing Potential

Premenopausal women who have not undergone a hysterectomy or oophorectomy must use effective contraception while using MULTAQ. Dronedarone caused fetal harm in animal studies at doses equivalent to recommended human doses. Counsel women of childbearing potential regarding appropriate contraceptive choices [see Use In Specific Populations].

Patient Counseling Information

Information for Patients

[See Medication Guide]

MULTAQ should be administered with a meal. Warn patients not to take MULTAQ with grapefruit juice.

If a dose is missed, patients should take the next dose at the regularly scheduled time and should not double the dose.

Advise patients to consult a physician before stopping treatment with MULTAQ.

Advise patients to consult a physician if they develop signs or symptoms of heart failure such as acute weight gain, dependent edema, or increasing shortness of breath.

Advise patients to immediately report any symptoms of potential liver injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant abdominal discomfort, jaundice, dark urine or itching) to their physician.

Advise patients to inform their physician of any history of heart failure, rhythm disturbance other than atrial fibrillation or flutter or predisposing conditions such as uncorrected hypokalemia.

MULTAQ may interact with some drugs; therefore, advise patients to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John's wort.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

In studies in which dronedarone was administered to rats and mice for up to 2 years at doses of up to 70 mg/kg/day and 300 mg/kg/day, respectively, there was an increased incidence of histiocytic sarcomas in dronedarone-treated male mice (300 mg/kg/day or 5X the maximum recommended human dose based on AUC comparisons), mammary adenocarcinomas in dronedarone-treated female mice (300 mg/kg/day or 8X MRHD based on AUC comparisons) and hemangiomas in dronedarone-treated male rats (70 mg/kg/day or 5X MRHD based on AUC comparisons).

Dronedarone did not demonstrate genotoxic potential in the in vivo mouse micronucleus test, the Ames bacterial mutation assay, the unscheduled DNA synthesis assay, or an in vitro chromosomal aberration assay in human lymphocytes. S-9 processed dronedarone, however, was positive in a V79 transfected Chinese hamster V79 assay.

In fertility studies conducted with female rats, dronedarone given prior to breeding and implantation caused an increase in irregular estrus cycles and cessation of cycling at doses ≥ 10mg/kg (equivalent to 0.12X the MRHD on a mg/m²basis).

Corpora lutea, implantations and live fetuses were decreased at 100 mg/kg (equivalent to 1.2X the MRHD on a mg/m²basis). There were no reported effects on mating behavior or fertility of male rats at doses of up to 100 mg/kg/day.

Use In Specific Populations

Pregnancy

Pregnancy Category X [see CONTRAINDICATIONS]

MULTAQ may cause fetal harm when administered to a pregnant woman. In animal studies, dronedarone was teratogenic in rats at the maximum recommended human dose (MRHD), and in rabbits at half the MRHD. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

When pregnant rats received dronedarone at oral doses greater than or equal to the MRHD (on a mg/m²basis), 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, ectrodactylia, syndactylia, and anterior and/or posterior club feet). When pregnant rabbits received dronedarone, at a dose approximately half the MRHD (on a mg/m²basis), 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)

Nursing Mothers

It is not known whether MULTAQ is excreted in human milk. Dronedarone and its metabolites are excreted in rat milk. During a pre- and post-natal study in rats, maternal dronedarone administration was associated with minor reduced body-weight gain in the offspring. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from MULTAQ, discontinue nursing or discontinue the drug [see CONTRAINDICATIONS].

Pediatric Use

Safety and efficacy in children below the age of 18 years have not been established.

Geriatric Use

More than 4500 patients with AF or AFL aged 65 years or above were included in the MULTAQ clinical program (of whom more than 2000 patients were 75 years or older). Efficacy and safety were similar in elderly and younger patients.

Renal Impairment

Patients with renal impairment were included in clinical studies. Because renal excretion of dronedarone is minimal [see CLINICAL PHARMACOLOGY], no dosing alteration is needed.

Hepatic Impairment

Dronedarone is extensively metabolized by the liver. There is little clinical experience with moderate hepatic impairment and none with severe impairment. No dosage adjustment is recommended for moderate hepatic impairment [see CONTRAINDICATIONS and CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

OVERDOSE

In the event of overdosage, monitor the patient's cardiac rhythm and blood pressure. Treatment should be supportive and based on symptoms.

It is not known whether dronedarone or its metabolites can be removed by dialysis (hemodialysis, peritoneal dialysis or hemofiltration). There is no specific antidote available.

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 and WARNINGS AND PRECAUTIONS]
  • Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [see BOXED WARNING and WARNINGS AND PRECAUTIONS]
  • 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 CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see DRUG INTERACTIONS]
  • Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine anti-psychotics, tricyclic antidepressants, certain oral macrolide antibiotics, and Class I and III antiarrhythmics
  • Liver or lung toxicity related to the previous use of amiodarone
  • QTc Bazett interval ≥ 500 ms or PR interval > 280 ms
  • Severe hepatic impairment
  • Pregnancy (Category X): MULTAQ may cause fetal harm when administered to a pregnant woman. MULTAQ is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations].
  • Nursing mothers [see Use In Specific Populations]
  • Hypersensitivity to the active substance or to any of the excipients

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

CLINICAL PHARMACOLOGY

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.

Pharmacodynamics

Electrophysiological effects

Dronedarone exhibits properties of all four Vaughn-Williams antiarrhythmic classes, although it is unclear which of these are important in producing dronedarone's clinical effects. The effect of dronedarone on 12-lead ECG parameters (heart rate, PR, and QTc) was investigated in healthy subjects following repeated oral doses up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. In the dronedarone 400 mg twice daily group, there was no apparent effect on heart rate; a moderate heart rate lowering effect (about 4 bpm) was noted at 800 mg twice daily. There was a clear dose-dependent effect on PR-interval with an increase of +5 ms at 400 mg twice daily and up to +50 ms at 1600 mg twice daily. There was a moderate dose related effect on the QTc-interval with an increase of +10 ms at 400 mg twice daily and up to +25 ms with 1600 mg twice daily.

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.

Pharmacokinetics

Dronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is increased by meals. Its elimination half life is 13-19 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 Cmax 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 2-fold increase in dose results in an approximate 2.5- to 3.0- fold increase with respect to Cmax 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 CYP 3A. 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. The N-debutyl metabolite exhibits pharmacodynamic activity but is 1/10 to 1/3 as potent as dronedarone.

Excretion/Elimination

In 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 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 a 2-fold higher 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].

Hepatic impairment

In subjects with moderate hepatic impairment, the mean dronedarone exposure increased by 1.3fold 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].

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]. 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 CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6. Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6. 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]. In vitro studies demonstrate that dronedarone or its metabolites are weak inhibitors of organic cation transporter (OCT1), organic anion transporting polypeptide (OATP1B1, OATP1B3), and organic anion transporter (OAT3). Monamine oxidases contribute partially to the metabolism of the active metabolite of dronedarone.

Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on dronedarone) and Figure 2 (impact of dronedarone on coadministered drugs).

Figure 1: The impact of co-administered drugs on the pharmacokinetics of dronedarone and recommendations for dronedarone coadministration or dose adjustment.

The impact of co-administered drugs on the pharmacokinetics of dronedarone and recommendations - Illustration

Figure 2: The impact of dronedarone on co-administered drugs and recommendations for dose adjustment of co-administered drug.

The impact of dronedarone on co-administered drugs and recommendations - Illustration

Developmental Toxicity

Dronedarone was teratogenic in rats given oral doses ≥ 80 mg/kg/day (a dose equivalent to the maximum recommended human dose [MHRD] on a mg/m²basis), with fetuses showing 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, ectrodactylia, syndactylia, and anterior and/or posterior club feet). In rabbits, dronedarone caused an increase in 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).

Clinical Studies

ATHENA

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%). Approximately seventy 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.

Table 3: Incidence of Endpoint Events

  Placebo (N= 2327) MULTAQ 400mg BID (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)
  • Cardiovascular hospitalization
856 (36.8%) 669 (29.1%)      
  • Death from any cause
57 (2.4%) 58 (2.5%)      
Secondary endpoints (any time in study)
  • Death from any cause
135 (5.8%) 115 (5.0%) 0.86 [0.67 - 1.11] 0.24
  • Cardiovascular hospitalization
856 (36.8%) 669 (29.1%) 0.74 [0.67 - 0.82] < 0.0001
Components of the cardiovascular hospitalization endpoint (as first event)
  • AF and other supraventricular rhythm disorders
456 (19.6%) 292 (12.7%) 0.61 [0.53 - 0.71] < 0.0001
  • Other
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.

Figure 3: Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from any Cause

Kaplan-Meier Cumulative Incidence Curves - Illustration

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).

Figure 4: Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from any Cause.

Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals - Illustration

EURIDIS and ADONIS

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 co-morbidities 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.

ANDROMEDA

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 vs. 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 vs. placebo groups.

There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo) [see BOXED WARNING and CONTRAINDICATIONS].

PALLAS

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 vs. 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 vs. placebo groups.
  • Stroke: 23 dronedarone vs. 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].
  • Hospitalizations for heart failure in the dronedarone group: 43 dronedarone vs. 24 placebo (HR, 1.81; CI: 1.10 to 2.99).

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

PATIENT INFORMATION

Medication Guide

MULTAQ
(MUL-tak)
(dronedarone) Tablets

Read this Medication Guide before you start taking MULTAQ and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about MULTAQ?

MULTAQ can cause serious side effects.

1. have symptoms of heart failure that recently worsened and you were hospitalized, or if you have severe heart failure.

MULTAQ doubles your risk of dying if you have these conditions.

Call your doctor right away if you have any signs or symptoms of heart failure during treatment with MULTAQ:

  • shortness of breath or wheezing at rest
  • wheezing, chest tightness or coughing up frothy sputum at rest, nighttime or after minor exercise
  • trouble sleeping or waking up at night because of breathing problems
  • using more pillows to prop yourself up at night so you can breathe more easily
  • gaining more than 5 pounds quickly
  • increasing swelling of feet or legs

2. have a type of atrial fibrillation (irregular heart rhythm) called permanent atrial fibrillation (AF).

Your doctor will monitor your heart rhythm regularly to make sure your

Call your doctor right away if you notice that your pulse is irregular during treatment with MULTAQ. This is a sign that you are in atrial fibrillation.

MULTAQ may cause liver problems, including life-threatening liver failure. Your doctor may order blood tests to check your liver before you start taking MULTAQ and during treatment. In some cases MULTAQ treatment may need to be stopped.

Call your doctor right away if you develop any of these signs and symptoms of liver problems during treatment with MULTAQ:

  • loss of appetite, nausea, vomiting
  • fever, feeling unwell, unusual tiredness
  • itching
  • yellowing of the skin or the whites of the eyes (jaundice)
  • unusual darkening of the urine
  • right upper stomach area pain or discomfort

What is MULTAQ?

MULTAQ is a prescription medicine used to lower the chance that you will need to go into the hospital for atrial fibrillation. It is meant for people who have had certain types of atrial fibrillation (paroxysmal or persistent AF) in the past, but are now in normal rhythm.

It is not known if MULTAQ is safe and effective in children younger than age 18 years old.

Who should not take MULTAQ?

See “What is the most important information I should know about taking MULTAQ?”

Do not take MULTAQ if:

  • you have a certain type of heart problem called heart block, and you do not have an implanted pacemaker
  • you have a slow heart rate, less than 50 beats each minute
  • you have severe liver problems or had liver or lung problems after using amiodarone (a medicine for abnormal heart rhythm)
  • you take certain medicines that can change the amount of MULTAQ that gets into your body. Do not use these medicines with MULTAQ:
    • Nefazodone for depression
    • Norvir® (ritonavir) for HIV infection
    • Nizoral® (ketoconazole), and Sporanox® (itraconazole), and Vfend® (voriconazole) for fungal infections
    • Ketek® (telithromycin), Biaxin® (clarithromycin) for bacterial infections
    • Cyclosporine for organ transplant
  • You take certain medicines that can lead to a dangerous abnormal heart rhythm:
    • Some medicines for mental illness called phenothiazines
    • Some medicines for depression called tricyclic antidepressants
    • Some medicines for abnormal heart rhythm or fast heartbeat
  • Some medicines for bacterial infection

Ask your doctor if you are not sure if your medicine is one that is listed above.

  • You are pregnant or plan to become pregnant. It is not known if MULTAQ will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
    • Women who may become pregnant should use effective birth control (contraception) while taking MULTAQ. Talk to your doctor about the best birth control methods for you.
  • You are breast-feeding or plan to breastfeed. It is not known if MULTAQ passes into your breast milk. You and your doctor should decide if you will take MULTAQ or breastfeed. You should not do both.
  • You are allergic to dronedarone or any of the other ingredients in MULTAQ. See the end of this Medication Guide for a complete list of ingredients in MULTAQ.

What should I tell my doctor before taking MULTAQ?

Before taking MULTAQ, tell your doctor if you:

  • have any other heart problems
  • Have any other medical conditions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. MULTAQ and certain other medicines can react with each other, causing serious side effects.

Especially tell your doctor and pharmacist if you take:

  • medicine for high blood pressure, chest pain, or other heart conditions
  • statin medicine to lower blood cholesterol
  • medicine for TB (tuberculosis)
  • medicine for seizures
  • digoxin (Lanoxin)
  • warfarin (Coumadin, Jantoven), a blood thinner medicine
  • medicine for organ transplant
  • herbal supplement called St. John's wort

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take MULTAQ?

  • Take MULTAQ exactly as your doctor tells you.
  • Take MULTAQ two times a day with food, once with your morning meal and once with your evening meal.
  • Do not stop taking MULTAQ without first talking to your doctor, even if you are feeling well for a long time.
  • If you miss a dose, wait and take your next dose at your regular time. Do not take 2 doses at the same time. Do not try to make up for a missed dose.
  • If you take too much MULTAQ, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking MULTAQ?

Do not drink grapefruit juice while you are being treated with MULTAQ. Grapefruit juice can increase the amount of MULTAQ in your blood and increase the likelihood that you will have a side effect of MULTAQ.

What are the possible side effects of MULTAQ?

MULTAQ may cause serious side effects, including:

  • See “What is the most important information I should know about MULTAQ?”
  • Slowed heartbeat (bradycardia)
  • Inflammation of the lungs, including scarring and thickening. Call your doctor if you develop shortness of breath or a dry cough during treatment with MULTAQ.
  • Low potassium and magnesium levels in your blood. This can happen if you take certain water pills (diuretics) during treatment with MULTAQ. Your doctor may check you for this problem before and during treatment.
  • Changes in kidney function blood tests after starting MULTAQ. Your doctor may check you for this during treatment.

The most common side effects of MULTAQ include:

  • diarrhea
  • nausea
  • vomiting
  • stomach area (abdominal) pain
  • indigestion
  • feeling tired and weak
  • skin problems such as redness, rash, and itching

Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects of MULTAQ. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store MULTAQ?

Store MULTAQ at room temperature (59 - 86°F or 15 - 30°C).

Keep MULTAQ and all medicines out of the reach of children.

General information about MULTAQ

Medicines are sometimes used for purposes other than those listed in a Medication Guide. Do not use MULTAQ for a condition for which it was not prescribed. Do not give MULTAQ to other people, even if they have the same symptoms or condition. It may harm them.

This Medication Guide summarizes the most important information about MULTAQ. If you would like more information:

Talk with your doctor

Ask your doctor or pharmacist for information about MULTAQ that was written for health-care professionals

For the latest information and Medication Guide, visit www.sanofi-aventis.us or call sanofi-aventis Medical Information Services at 1-800-633- 1610 option 1. The Medication Guide may have changed since this copy was printed.

What are the ingredients in MULTAQ?

Active ingredient: dronedarone

Inactive ingredients: hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate, polyethylene glycol 6000, titanium dioxide, carnauba wax

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

>

PATIENT INFORMATION

Medication Guide

MULTAQ
(MUL-tak)
(dronedarone) Tablets

Read this Medication Guide before you start taking MULTAQ and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment.

What is the most important information I should know about MULTAQ?

MULTAQ can cause serious side effects.

1. have symptoms of heart failure that recently worsened and you were hospitalized, or if you have severe heart failure.

MULTAQ doubles your risk of dying if you have these conditions.

Call your doctor right away if you have any signs or symptoms of heart failure during treatment with MULTAQ:

  • shortness of breath or wheezing at rest
  • wheezing, chest tightness or coughing up frothy sputum at rest, nighttime or after minor exercise
  • trouble sleeping or waking up at night because of breathing problems
  • using more pillows to prop yourself up at night so you can breathe more easily
  • gaining more than 5 pounds quickly
  • increasing swelling of feet or legs

2. have a type of atrial fibrillation (irregular heart rhythm) called permanent atrial fibrillation (AF).

Your doctor will monitor your heart rhythm regularly to make sure your

Call your doctor right away if you notice that your pulse is irregular during treatment with MULTAQ. This is a sign that you are in atrial fibrillation.

MULTAQ may cause liver problems, including life-threatening liver failure. Your doctor may order blood tests to check your liver before you start taking MULTAQ and during treatment. In some cases MULTAQ treatment may need to be stopped.

Call your doctor right away if you develop any of these signs and symptoms of liver problems during treatment with MULTAQ:

  • loss of appetite, nausea, vomiting
  • fever, feeling unwell, unusual tiredness
  • itching
  • yellowing of the skin or the whites of the eyes (jaundice)
  • unusual darkening of the urine
  • right upper stomach area pain or discomfort

What is MULTAQ?

MULTAQ is a prescription medicine used to lower the chance that you will need to go into the hospital for atrial fibrillation. It is meant for people who have had certain types of atrial fibrillation (paroxysmal or persistent AF) in the past, but are now in normal rhythm.

It is not known if MULTAQ is safe and effective in children younger than age 18 years old.

Who should not take MULTAQ?

See “What is the most important information I should know about taking MULTAQ?”

Do not take MULTAQ if:

  • you have a certain type of heart problem called heart block, and you do not have an implanted pacemaker
  • you have a slow heart rate, less than 50 beats each minute
  • you have severe liver problems or had liver or lung problems after using amiodarone (a medicine for abnormal heart rhythm)
  • you take certain medicines that can change the amount of MULTAQ that gets into your body. Do not use these medicines with MULTAQ:
    • Nefazodone for depression
    • Norvir® (ritonavir) for HIV infection
    • Nizoral® (ketoconazole), and Sporanox® (itraconazole), and Vfend® (voriconazole) for fungal infections
    • Ketek® (telithromycin), Biaxin® (clarithromycin) for bacterial infections
    • Cyclosporine for organ transplant
  • You take certain medicines that can lead to a dangerous abnormal heart rhythm:
    • Some medicines for mental illness called phenothiazines
    • Some medicines for depression called tricyclic antidepressants
    • Some medicines for abnormal heart rhythm or fast heartbeat
  • Some medicines for bacterial infection

Ask your doctor if you are not sure if your medicine is one that is listed above.

  • You are pregnant or plan to become pregnant. It is not known if MULTAQ will harm your unborn baby. Talk to your doctor if you are pregnant or plan to become pregnant.
    • Women who may become pregnant should use effective birth control (contraception) while taking MULTAQ. Talk to your doctor about the best birth control methods for you.
  • You are breast-feeding or plan to breastfeed. It is not known if MULTAQ passes into your breast milk. You and your doctor should decide if you will take MULTAQ or breastfeed. You should not do both.
  • You are allergic to dronedarone or any of the other ingredients in MULTAQ. See the end of this Medication Guide for a complete list of ingredients in MULTAQ.

What should I tell my doctor before taking MULTAQ?

Before taking MULTAQ, tell your doctor if you:

  • have any other heart problems
  • Have any other medical conditions

Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. MULTAQ and certain other medicines can react with each other, causing serious side effects.

Especially tell your doctor and pharmacist if you take:

  • medicine for high blood pressure, chest pain, or other heart conditions
  • statin medicine to lower blood cholesterol
  • medicine for TB (tuberculosis)
  • medicine for seizures
  • digoxin (Lanoxin)
  • warfarin (Coumadin, Jantoven), a blood thinner medicine
  • medicine for organ transplant
  • herbal supplement called St. John's wort

Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine.

How should I take MULTAQ?

  • Take MULTAQ exactly as your doctor tells you.
  • Take MULTAQ two times a day with food, once with your morning meal and once with your evening meal.
  • Do not stop taking MULTAQ without first talking to your doctor, even if you are feeling well for a long time.
  • If you miss a dose, wait and take your next dose at your regular time. Do not take 2 doses at the same time. Do not try to make up for a missed dose.
  • If you take too much MULTAQ, call your doctor or go to the nearest hospital emergency room right away.

What should I avoid while taking MULTAQ?

Do not drink grapefruit juice while you are being treated with MULTAQ. Grapefruit juice can increase the amount of MULTAQ in your blood and increase the likelihood that you will have a side effect of MULTAQ.

What are the possible side effects of MULTAQ?

MULTAQ may cause serious side effects, including:

  • See “What is the most important information I should know about MULTAQ?”
  • Slowed heartbeat (bradycardia)
  • Inflammation of the lungs, including scarring and thickening. Call your doctor if you develop shortness of breath or a dry cough during treatment with MULTAQ.
  • Low potassium and magnesium levels in your blood. This can happen if you take certain water pills (diuretics) during treatment with MULTAQ. Your doctor may check you for this problem before and during treatment.
  • Changes in kidney function blood tests after starting MULTAQ. Your doctor may check you for this during treatment.

The most common side effects of MULTAQ include:

  • diarrhea
  • nausea
  • vomiting
  • stomach area (abdominal) pain
  • indigestion
  • feeling tired and weak
  • skin problems such as redness, rash, and itching

Tell your doctor about any side effect that bothers you or that does not go away. These are not all the possible side effects of MULTAQ. For more information ask your doctor or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store MULTAQ?

Store MULTAQ at room temperature (59 - 86°F or 15 - 30°C).

Keep MULTAQ and all medicines out of the reach of children.

General information about MULTAQ

Medicines are sometimes used for purposes other than those listed in a Medication Guide. Do not use MULTAQ for a condition for which it was not prescribed. Do not give MULTAQ to other people, even if they have the same symptoms or condition. It may harm them.

This Medication Guide summarizes the most important information about MULTAQ. If you would like more information:

Talk with your doctor

Ask your doctor or pharmacist for information about MULTAQ that was written for health-care professionals

For the latest information and Medication Guide, visit www.sanofi-aventis.us or call sanofi-aventis Medical Information Services at 1-800-633- 1610 option 1. The Medication Guide may have changed since this copy was printed.

What are the ingredients in MULTAQ?

Active ingredient: dronedarone

Inactive ingredients: hypromellose, starch, crospovidone, poloxamer 407, lactose monohydrate, colloidal silicon dioxide, magnesium stearate, polyethylene glycol 6000, titanium dioxide, carnauba wax

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Last reviewed on RxList: 9/20/2012
This monograph has been modified to include the generic and brand name in many instances.

Disclaimer

Multaq Consumer

IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs.

DRONEDARONE - ORAL

(DROE-NE-da-rone)

COMMON BRAND NAME(S): Multaq

WARNING: This medication should not be used by people with certain kinds of heart failure (such as people with NYHA Class IV heart failure, people with recent worsening of heart failure) or a certain kind of irregular heartbeat (permanent atrial fibrillation). Consult your doctor for more details. Tell your doctor immediately if you have new or worsening symptoms of heart failure, including shortness of breath, wheezing, unusual tiredness, swelling ankles/feet, unusual weight gain.

Talk to your doctor about the risks and benefits of dronedarone.

USES: This medication is used by people with a history of certain types of irregular heartbeat (paroxysmal or persistent atrial fibrillation). It helps to reduce the risk of going to the hospital for atrial fibrillation. Dronedarone is known as an antiarrhythmic drug.

This medication should not be used by people with a certain type of irregular heartbeat (permanent atrial fibrillation) due to the increased risk of serious side effects.

HOW TO USE: Read the Medication Guide provided by your pharmacist before you start using dronedarone and each time you get a refill. If you have any questions, consult your doctor or pharmacist.

Take this medication by mouth, usually twice daily, once with your morning meal and once with your evening meal, or as directed by your doctor.

Use this medication regularly in order to get the most benefit from it. To help you remember, take it at the same times each day. Your doctor may also direct you to take another medication ("blood thinner") along with this medication. Follow your doctor's instructions carefully.

Avoid eating grapefruit or drinking grapefruit juice while using this medication unless your doctor instructs you otherwise. Grapefruit can increase the amount of this medication in your bloodstream. Consult your doctor or pharmacist for more details.

Tell your doctor if your condition persists or worsens (such as your pulse becomes irregular).

Disclaimer

Multaq Consumer (continued)

SIDE EFFECTS: See also Warning section.

Nausea or diarrhea may occur. If any of these effects persist or worsen, tell your doctor promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: symptoms of liver disease (such as dark urine, persistent nausea/vomiting, severe stomach/abdominal pain, yellowing eyes/skin).

Seek immediate medical attention if any of these rare but serious side effects occur: unusually fast/slow/irregular heartbeat, severe dizziness, fainting.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

Read the Multaq (dronedarone tablets) Side Effects Center for a complete guide to possible side effects »

PRECAUTIONS: See also Warning section.

Before taking dronedarone, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies. This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, certain types of irregular heartbeat (sick sinus syndrome, second- or third-degree atrioventricular block), serious side effects (such as liver/lung disease) from taking the medication amiodarone.

Dronedarone may cause a condition that affects the heart rhythm (QT prolongation). QT prolongation can infrequently result in serious (rarely fatal) fast/irregular heartbeat and other symptoms (such as severe dizziness, fainting) that require immediate medical attention. The risk of QT prolongation may be increased if you have certain medical conditions or are taking other drugs that may affect the heart rhythm (see also Drug Interactions section). Before using dronedarone, tell your doctor or pharmacist if you have any of the following conditions: certain heart problems (heart failure, slow heartbeat, QT prolongation in the EKG), family history of certain heart problems (QT prolongation in the EKG, sudden cardiac death).

Low levels of potassium or magnesium in the blood may also increase your risk of QT prolongation. This risk may increase if you use certain drugs (such as diuretics/"water pills") or if you have conditions such as severe sweating, diarrhea, or vomiting. Talk to your doctor about using dronedarone safely.

Before having surgery, tell your doctors or dentist about all the products you use (including prescription drugs, nonprescription drugs, and herbal products).

This medication must not be used during pregnancy. It may harm an unborn baby. Discuss the use of reliable forms of birth control with your doctor. If you become pregnant or think you may be pregnant, tell your doctor immediately.

It is unknown if this medication passes into breast milk. Because of the possible risk to the infant, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

Disclaimer

Multaq Consumer (continued)

DRUG INTERACTIONS: See also How to Use section.

Drug interactions may change how your medications work or increase your risk for serious side effects. This document does not contain all possible drug interactions. Keep a list of all the products you use (including prescription/nonprescription drugs and herbal products) and share it with your doctor and pharmacist. Do not start, stop, or change the dosage of any medicines without your doctor's approval.

A product that may interact with this drug is: fingolimod.

Many drugs besides dronedarone may affect the heart rhythm (QT prolongation). Examples include amiodarone, dofetilide, pimozide, procainamide, quinidine, sotalol, among others.

Other medications can affect the removal of dronedarone from your body, which may affect how dronedarone works. Examples include azole antifungals (such as ketoconazole, itraconazole, voriconazole), cyclosporine, macrolide antibiotics (such as clarithromycin, erythromycin), nefazodone, HIV protease inhibitors (such as ritonavir), rifamycins (such as rifabutin), St. John's wort, drugs used to treat seizures (such as carbamazepine, phenytoin), telithromycin, among others.

Dronedarone can slow down the removal of other medications from your body, which may affect how they work. Examples of affected drugs include certain "statin" drugs (atorvastatin, lovastatin, simvastatin), warfarin, tacrolimus, sirolimus, digoxin, dabigatran, among others.

OVERDOSE: If overdose is suspected, contact a poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as EKG, kidney/liver function, blood mineral levels including potassium) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details. Keep all laboratory and medical appointments.

MISSED DOSE: If you miss a dose, skip the missed dose and take your next dose at your regular scheduled time. Do not double the dose to catch up.

STORAGE: Store at room temperature away from light and moisture. Do not store in the bathroom. Keep all medications away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (US), or 1-800-668-1507 (Canada).

Information last revised May 2012. Copyright(c) 2012 First Databank, Inc.

Multaq Patient Information Including Side Effects

Brand Names: Multaq

Generic Name: dronedarone (Pronunciation: droe NE da rone)

What is dronedarone (Multaq)?

Dronedarone is an antiarrhythmic medication that affects the rhythm of heartbeats.

Dronedarone helps keep the heart beating normally in people with life-threatening heart rhythm disorders of the atrium (the upper chambers of the heart that allow blood to flow into the heart) and risk factors such as diabetes, high blood pressure, a history of stroke, or being over 70 years old.

Dronedarone is used to treat certain heart rhythm disorders called atrial fibrillation or atrial flutter. Dronedarone is given to reduce the need for hospitalization due to these heart conditions.

Dronedarone may also be used for purposes not listed in this medication guide.

Multaq 400 mg

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What are the possible side effects of dronedarone (Multaq)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have a serious side effect such as:

  • severe dizziness, fainting, fast or pounding heartbeats;
  • slow heart rate, feeling like you might pass out;
  • a new or a worsening irregular heartbeat pattern;
  • feeling short of breath, even with mild exertion, swelling in your ankles or feet, rapid weight gain;
  • wheezing, cough, chest pain, trouble breathing, coughing up mucus;
  • nausea, upper stomach pain, itching, loss of appetite, dark urine, clay-colored stools, jaundice (yellowing of the skin or eyes);
  • breathing problems while lying down trying to sleep; or
  • low electrolytes (confusion, jerky muscle movements, uneven heartbeats, extreme thirst, increased urination, leg discomfort, muscle weakness or limp feeling).

Less serious side effects may include:

  • mild stomach pain, diarrhea, upset stomach;
  • feeling weak or tired; or
  • mild skin rash or redness.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the Multaq (dronedarone tablets) Side Effects Center for a complete guide to possible side effects »

What is the most important information I should know about dronedarone (Multaq)?

Dronedarone is used to treat intermittent or "temporary" heart rhythm disorders. In some people with "permanent" atrial fibrillation, dronedarone increased the risk of stroke, hospitalization due to heart failure, and death. Talk with your doctor about your individual risk. Do not stop taking this medication without first talking to your doctor. Stopping suddenly may make your condition worse.

You should not use dronedarone if you are allergic to dronedarone, if you are pregnant or breast-feeding, or if you have severe liver disease, certain serious heart conditions, especially severe heart failure, "AV block" or sick sinus syndrome (unless you have a pacemaker), a history of slow heart beats that have caused you to faint, or if you were recently hospitalized for heart failure.

Also tell your doctor if you have kidney disease, liver disease, a history of heart failure, an electrolyte imbalance (such as low levels of potassium or magnesium in your blood), or if you have a pacemaker or defibrillator implanted in your chest.

You may need regular medical tests to be sure this medication is not causing harmful effects. Visit your doctor regularly.

Side Effects Centers

Multaq Patient Information including How Should I Take

What should I discuss with my healthcare provider before taking dronedarone (Multaq)?

Dronedarone is used to treat intermittent or "temporary" heart rhythm disorders. In some people with "permanent" atrial fibrillation, dronedarone increased the risk of stroke, hospitalization due to heart failure, and death. Talk with your doctor about your individual risk. Do not stop taking this medication without first talking to your doctor. Stopping suddenly may make your condition worse.

You should not use this medication if you are allergic to dronedarone, or if you have:

  • severe liver disease;
  • certain serious heart conditions, especially severe heart failure, "AV block" or sick sinus syndrome (unless you have a pacemaker);
  • a history of slow heart beats that have caused you to faint;
  • if you were hospitalized with severe heart failure within the past 30 days; or
  • if you are pregnant or breast-feeding.
  • heart rhythm medication;
  • an antibiotic or antifungal medication;
  • an antidepressant;
  • medicine to treat HIV or AIDS;
  • medicine to treat or prevent malaria;
  • medicine to treat a psychiatric disorder;
  • migraine headache medication;
  • narcotic pain medicine;
  • medicine to prevent or treat nausea and vomiting; or
  • medicine used to prevent organ transplant rejection.

To make sure you can safely take dronedarone, tell your doctor if you have any of these other conditions:

  • kidney disease;
  • liver disease;
  • a history of heart failure;
  • an electrolyte imbalance (such as low levels of potassium or magnesium in your blood); or
  • if you have a pacemaker or defibrillator implanted in your chest.

FDA pregnancy category X. This medication can harm an unborn baby or cause birth defects. Do not use dronedarone if you are pregnant. Tell your doctor right away if you become pregnant during treatment. Use effective birth control while you are using this medication.

It is not known whether dronedarone passes into breast milk or if it could harm a nursing baby. You should not breast-feed while taking dronedarone.

How should I take dronedarone (Multaq)?

Take exactly as prescribed by your doctor. Do not take in larger or smaller amounts or for longer than recommended. Follow the directions on your prescription label.

Dronedarone works best if you take it with your morning and evening meals.

Use dronedarone regularly even if you feel fine or have no symptoms. Get your prescription refilled before you run out of medicine completely.

Do not stop taking this medication without first talking to your doctor.

To be sure this medication is not causing harmful effects, your blood and heart rhythm will need to be tested often. Your liver and kidney function may also need to be tested. Visit your doctor regularly.

Store at room temperature away from heat and moisture.

Side Effects Centers

Multaq Patient Information including If I Miss a Dose

What happens if I miss a dose (Multaq)?

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

What happens if I overdose (Multaq)?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking dronedarone (Multaq)?

Grapefruit and grapefruit juice may interact with dronedarone and lead to potentially dangerous effects. Discuss the use of grapefruit products with your doctor.

What other drugs will affect dronedarone (Multaq)?

Many drugs can interact with dronedarone and some should not be used at the same time. Below is only a partial list of these drugs. Tell your doctor if you are using:

  • a blood thinner such as warfarin (Coumadin, Jantoven);
  • cyclosporine (Gengraf, Neoral, Sandimmune);
  • digoxin (digitalis, Lanoxin, Lanoxicaps);
  • sirolimus (Rapamune) or tacrolimus (Prograf);
  • St. John's wort;
  • theophylline (Elixophyllin, Theo-24, Uniphyl);
  • tuberculosis medications;
  • a beta-blocker such as atenolol (Tenormin), bisoprolol (Zebeta, Ziac), metoprolol (Lopressor, Toprol), propranolol (Inderal, InnoPran), and others;
  • cholesterol-lowering medicines such as cholestyramine (Prevalite, Questran), atorvastatin (Lipitor), simvastatin (Zocor), lovastatin (Mevacor), pravastatin (Pravachol), or fluvastatin (Lescol);
  • heart or blood pressure medication such as amlodipine (Norvasc), diltiazem (Cardizem, Dilacor, Tiazac), felodipine (Plendil), nifedipine (Procardia, Adalat), verapamil (Calan, Covera, Isoptin, Verelan), and others; or
  • seizure medication such as carbamazepine (Carbatrol, Equetro, Tegretol), phenytoin (Dilantin), and others.

Where can I get more information?

Your pharmacist can provide more information about dronedarone.


Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2012 Cerner Multum, Inc. Version: 6.01. Revision date: 10/14/2011.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

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Side Effects Centers

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