Pill Identifier App

Label Changes for:

Multaq (dronedarone hydrochloride) Tablets

March 2013

Changes have been made to the ADVERSE REACTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) 

 

March 2013

ADVERSE REACTIONS

Postmarketing Experience
  • Atrial flutter with 1:1 atrioventricular conduction has been reported very rarely.
     

 

September 2012

CONTRAINDICATIONS

added:
 

  • Liver or lung toxicity.... 
  • Hypersensitivity to the active substance or to any of the excipients

5 WARNINGS AND PRECAUTIONS

5.6 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 .....

6 ADVERSE REACTIONS

6.2 Adverse Reactions/Postmarketing Experience
  • 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

7.1 Drug Interactions/Pharmacodynamic Interactions
  • 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.
7.2 Drug Interactions/Effects of Dronedarone on Other Drugs/P-glycoprotein substrates/Digoxin
  • Consider discontinuing digoxin

MEDICATION GUIDE

What are the possible side effects of MULTAQ,”:

  • 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

 

 

January 2012

7 DRUG INTERACTIONS

7.1 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 .....

Digoxin

  • Digoxin can potentiate the electrophysiologic effects of dronedarone (such as decreased AV-node conduction). In clinical trials, increase.....

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 ......

Beta-blockers

  • In clinical trials, bradycardia was more frequently observed when dronedarone was given in combination with beta-blockers. Give a low dose.....
7.2 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 ......

Grapefruit juice

  • Patients should avoid grapefruit juice beverages.....

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 .....

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 .....
7.3 Effects of Dronedarone on Other Drugs

Simvastatin

  • Dronedarone increased simvastatin/simvastatin acid exposure. Avoid.....

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. Reconsider the need for digoxin therapy. 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 ......Monitor INR after initiating dronedarone in patients taking warfarin. 

 

 

December 2011 

 

BOXED WARNING

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

 

CONTRAINDICATIONS

MULTAQ is contraindicated in patients with:
  • Permanent atrial fibrillation (patients in whom normal sinus rhythm will not or cannot be restored).
  • Symptomatic heart failure with recent decompensation requiring hospitalization or NYHA Class IV symptoms.

 

WARNINGS AND 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. Multaq should only be initiated in patients in sinus rhythm who are receiving appropriate antithrombotic therapy.
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.

 

ADVERSE REACTIONS

Post Marketing Experience
  • Cardiac: New or worsening heart failure
  • Hepatic: Liver Injury
Medication Guide

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

  • Multaq is not for people with heart failure with symptoms which recently worsened or for people with severe heart failure. People with these conditions who take Multaq have an increased chance of dying. Heart failure means your heart does not pump blood through your body as well as it should.
  • Call your doctor right away if you have any signs and symptoms of heart failure...
  • Multaq is not for people with a type of atrial fibrillation (irregular heart rhythm) called permanent atrial fibrillation (AF). In permanent AF, your heartbeat stays in atrial fibrillation and will not or cannot be changed back to a normal rhythm. Your doctor will monitor your heart rhythm regularly to make sure your heartbeat keeps a normal rhythm.
  • Do not take Multaq if you have symptoms of heart failure which recently worsened or if you have severe heart failure.
  • Do not take Multaq if you have permanent AF.
  • Multaq may cause liver problems, including life-threatening liver failure…

 

August 2011 

 

WARNINGS AND PRECAUTIONS

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.

 

June 2011

 

ADVERSE REACTION

Postmarketing Experience
  • Respiratory: Postmarketing cases of interstitial lung disease including pneumonitis and pulmonary fibrosis have been reported.

 

March 2011

DRUG INTERACTIONS

Effects of Dronedarone on Other Drugs
  • Warfarin and losartan (CYP 2C9 substrates) (section revised)
  • Losartan: No interaction was observed between dronedarone and losartan.
  • Warfarin: When healthy subjects were administered dronedarone 600 mg twice daily, exposure to S-warfarin was higher than when warfarin was administered alone (1.2-fold). Exposure to R-warfarin was unchanged and there were no clinically significant increases in INR. 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.

 

February 2011

 

WARNINGS AND PRECAUTIONS

Patients with New or Worsening Heart Failure
  • Postmarketing cases of new onset and worsening heart failure have been reported during treatment with Multaq. 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, consider the suspension or discontinuation of Multaq.
Liver Injury
  • Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with Multaq in the post-marketing 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. It is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. ...

ADVERSE REACTIONS

Postmarketing Experience
Hepatic
  • Serum hepatic enzymes and serum bilirubin increase: Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported.
Cardiac
  • Postmarketing cases of new onset and worsening heart failure have been reported during treatment with Multaq.

PATIENT COUNSELING INFORMATION

  • 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.

 

January 2011

 

7 DRUG INTERACTIONS

7.3 Effects of Dronedarone on Other Drugs

P-glycoprotein substrates

Digoxin

  • Dronedarone increased digoxin exposure by 2.5-fold by inhibiting the P-gP transporter [see Drug Interactions (7.1)].

Dabigatran

  • Exposure to dabigatran is higher when it is administered with dronedarone than when it is administered alone (1-7- to 2-fold).

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

Hide
(web4)