Dronedarone

Dronedarone
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sheng Shi, M.D. [2]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING See full prescribing information for complete Boxed Warning. To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. TIKOSYN is available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education; see DOSAGE AND ADMINISTRATION.

Overview

Dronedarone is an Antiarrhythmic that is FDA approved for the {{{indicationType}}} of atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation (AF). There is a Black Box Warning for this drug as shown here. Common adverse reactions include Abdominal pain, Diarrhea, Indigestion, Nausea, Vomiting, Asthenia , Serum creatinine raised.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Atrial Fibrillation

• Dosing Information

• 400 mg PO bid ( taken as one tablet with the morning meal and one tablet with the evening meal)

Off-Label Use and Dosage (Adult)

Non–Guideline-Supported Use

Atrial flutter, Paroxysmal or persistent

• Dosing information

• 400 mg/day PO

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Dronedarone FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

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 (5.2)]
• Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms [see Boxed Warning and 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 CYP 3A inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporine, telithromycin, clarithromycin, nefazodone, and ritonavir [see Drug Interactions (7.2)]
• Concomitant use of drugs or herbal products that prolong the QT interval and might increase the risk of Torsade de Pointes, such as phenothiazine 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 (8.1)].
• Nursing mothers [see Use in Specific Populations (8.3)]
• Hypersensitivity to the active substance or to any of the excipients

Warnings

WARNING See full prescribing information for complete Boxed Warning. To minimize the risk of induced arrhythmia, patients initiated or re-initiated on TIKOSYN should be placed for a minimum of 3 days in a facility that can provide calculations of creatinine clearance, continuous electrocardiographic monitoring, and cardiac resuscitation. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION. TIKOSYN is available only to hospitals and prescribers who have received appropriate TIKOSYN dosing and treatment initiation education; see DOSAGE AND ADMINISTRATION.

• 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 (14.4)]. MULTAQ should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy [see Drug interactions (7.3)].

• 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 (6.2)]. Onset of dyspnea or non-productive cough may be related to pulmonary toxicity and patients should be carefully evaluated clinically. If pulmonary toxicity is confirmed, MULTAQ should be discontinued.

• 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 (12.2) and Clinical Studies (14.1)]. If the QTc Bazett interval is ≥500 ms, discontinue MULTAQ [see Contraindications (4)].

• Renal Impairment and Failure

• Marked increase in serum creatinine, pre-renal azotemia and acute renal failure, often in the setting of heart failure [see Warnings and Precautions (5.4)] or hypovolemia, have been reported in patients taking MULTAQ. In most cases, these effects appear to be reversible upon drug discontinuation and with appropriate medical treatment. Monitor renal function periodically.
• Small increases in creatinine levels (about 0.1 mg/dL) following dronedarone treatment initiation have been shown to be a result of inhibition of creatinine's tubular secretion.

The elevation has a rapid onset, reaches a plateau after 7 days and is reversible after discontinuation.

• 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 (8.1)].

Adverse Reactions

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.

File:Dronedarone clinical trials 01.jpg

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.

File:Dronedarone clinical trials 01.jpg

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 (5.4)] Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely. Hepatic: Liver Injury [see Warnings and Precautions (5.5)] Respiratory: Interstitial lung disease including pneumonitis and pulmonary fibrosis [see Warnings and Precautions (5.6)] Immune: Anaphylactic reactions including angioedema Vascular: Vasculitis, including leukocytoclastic vasculitis

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 (4), Clinical Pharmacology (12.3)].

• Digoxin

• In the ANDROMEDA (patients with recently decompensated heart failure) and PALLAS (patients with permanent AF) trials baseline use of digoxin was associated with an increased risk of arrhythmic or sudden death in dronedarone-treated patients compared to placebo. In patients not taking digoxin, no difference in risk of sudden death was observed in the dronedarone vs. placebo groups. [See Clinical Trials (14.3)].
• Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). Dronedarone increases exposure to digoxin [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].
• Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity.

• Calcium channel blockers

• Calcium channel blockers with depressant effects on the sinus and AV nodes could potentiate dronedarone's effects on conduction.

• Give a low dose of calcium channel blockers initially and increase only after ECG verification of good tolerability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

• Beta-blockers

• In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers.

• Give a low dose of beta-blockers initially, and increase only after ECG verification of good tolerability [see Drug Interactions (7.3), Clinical Pharmacology (12.3)].

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 (4), Clinical Pharmacology (12.3)].

• Grapefruit juice

• Patients should avoid grapefruit juice beverages while taking MULTAQ because exposure to dronedarone is significantly increased [see Clinical Pharmacology (12.3)].

• Rifampin and other 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 (12.3)].

• 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 Drug Interactions (7.3), Clinical Pharmacology (12.3)].

Effects of Dronedarone on Other Drugs

• Simvastatin

• Dronedarone increased simvastatin/simvastatin acid exposure. Avoid doses greater than 10 mg once daily of simvastatin [see Clinical Pharmacology (12.3)].

• Other statins

• Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with 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 Drug Interactions (7.1), Clinical Pharmacology (12.3)].

• Sirolimus, tacrolimus, and other CYP3A substrates with narrow therapeutic range
• Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other 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 Drug Interactions (7.1), Clinical Pharmacology (12.3)].

• P-glycoprotein substrates

• Digoxin

• Dronedarone increased digoxin exposure by inhibiting the P-gp transporter. Consider discontinuing digoxin. If digoxin treatment is continued, halve the dose of digoxin, monitor serum levels closely, and observe for toxicity [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

• Dabigatran

• 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 (12.3)].
• 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.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Dronedarone in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Dronedarone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Dronedarone during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Dronedarone in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Dronedarone in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Dronedarone in geriatric settings.

Gender

There is no FDA guidance on the use of Dronedarone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Dronedarone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Dronedarone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Dronedarone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Dronedarone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Dronedarone in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Dronedarone Administration in the drug label.

Monitoring

There is limited information regarding Dronedarone Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Dronedarone and IV administrations.

Overdosage

There is limited information regarding Dronedarone overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

Mechanism of Action

There is limited information regarding Dronedarone Mechanism of Action in the drug label.

Structure

There is limited information regarding Dronedarone Structure in the drug label.

Pharmacodynamics

There is limited information regarding Dronedarone Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Dronedarone Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Dronedarone Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Dronedarone Clinical Studies in the drug label.

How Supplied

There is limited information regarding Dronedarone How Supplied in the drug label.

Storage

There is limited information regarding Dronedarone Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Dronedarone |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Dronedarone |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Dronedarone Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Dronedarone interaction has not been established. Talk to your doctor regarding the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Dronedarone Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Dronedarone Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Dronedarone

File:Dronedarone.svg
Legal status
Legal status	Phase III
Identifiers
IUPAC name N-(2-Butyl-3-(p-(3-(dibutylamino)propoxy)benzoyl)- 5-benzofuranyl)methanesulfonamide
CAS Number	141626-36-0
PubChem CID	208898
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C31H44N2O5S
Molar mass	556.758

Dronedarone (also known as SR33589) is a drug under development by Sanofi-Aventis, mainly for the indication of cardiac arrhythmias (irregular heartbeat). It is currently in phase III trials for atrial fibrillation and in patients with an implantable cardioverter-defibrillator (ICD); a trial in heart failure was stopped as an interim analysis showed a possible increase in heart failure deaths.

Chemically it is a benzofuran derivative related to amiodarone, a popular antiarrhythmic the use of which is limited to toxicity due its high iodine content (pulmonary fibrosis, thyroid disease) as well as by liver disease. Dronedarone lacks the iodine, and is expected to have less toxicity, yet it displays amiodarone-like class III antiarrhytmic activity in vitro and in clinical trials.

In a 2007 trial in atrial fibrillation, dronedarone was significantly more effective than placebo in maintaining sinus rhythm, with no difference in lung and thyroid function in the short term.