Dronedarone (Multaq▼): cardiovascular, hepatic and pulmonary adverse events – new restrictions and monitoring requirements

Following new evidence of cardiovascular, hepatic and pulmonary risk, a review of dronedarone has concluded that the benefits of treatment continue to outweigh the risks for the maintenance of sinus rhythm after successful cardioversion in a limited population of patients with paroxysmal or persistent atrial fibrillation; however, in light of safety concerns dronedarone should only be prescribed after other treatment options have been considered. To support safer use, patients should have their treatment reviewed at the next routine appointment to ensure that they remain eligible for dronedarone treatment according to the revised prescribing information, including new restrictions on use. Regular monitoring of cardiac, liver, and renal function during treatment is recommended

Article date: October 2011

Dronedarone (Multaq▼) is an antiarrhythmic agent available as a 400 mg film-coated tablet with a recommended dose of 400 mg twice daily.

Discontinuation of PALLAS study 

The PALLAS study (Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard therapy) had been investigating the potential clinical benefit of dronedarone (added to standard therapy) in patients older than 65 years with permanent atrial fibrillation in the reduction of:

  • major cardiovascular (CV) events (ie, stroke, systemic arterial embolism, myocardial infarction, or cardiovascular death)
  • unplanned cardiovascular hospitalisation or death from any cause

The study was prematurely terminated in July 2011, when an interim analysis showed a significant excess of CV-related deaths, stroke, and hospitalisations due to CV events in the dronedarone group compared with placebo.

Review of risks and benefits

A Europe-wide review of the risks and benefits of treatment with dronedarone began in January 2011 because of concerns over reports of liver injury, including two cases of liver failure requiring transplantation. Product information was updated to recommend monthly liver-function testing for the first 6 months of treatment, and at 9 and 12 months after treatment initiation (see Drug Safety Update, Feb 2011).

The review was extended to include CV and pulmonary safety after the premature termination of PALLAS and several reported cases of pulmonary injury which may be associated with dronedarone.

The review included data from PALLAS and postmarketing data for liver and pulmonary toxicity. The EU Committee for Medicinal Products for Human Use (CHMP) considered that the benefits of treatment now continue to outweigh the risks in a restricted patient population.

Revised indication

CHMP recommended that dronedarone should now be used only for the maintenance of sinus rhythm after successful cardioversion in patients with paroxysmal or persistent atrial fibrillation (AF). Because of safety concerns, dronedarone should only be prescribed after alternative treatment options have been considered. Dronedarone should not be given to patients with left ventricular systolic dysfunction, or to patients with current or previous episodes of heart failure.

CHMP considered that treatment with dronedarone should be initiated and monitored only under specialist supervision. A number of further contraindications for use and recommendations for monitoring were also endorsed by CHMP.

Advice for healthcare professionals:


Dronedarone is now contraindicated in patients with:

  • unstable haemodynamic conditions

  • history of, or current, heart failure or left ventricular systolic dysfunction

  • permanent AF (ie, duration ≥6 months or unknown, and attempts to restore sinus rhythm no longer considered by physician)

  • liver and lung toxicity related to previous use of amiodarone

Cardiovascular monitoring

Patients should receive regular cardiac examinations, including an ECG at least every 6 months, to identify those who revert to AF. Discontinuation of dronedarone should be considered for these patients.

Discontinue treatment if the patient develops permanent AF.

Patients should be carefully evaluated for symptoms of heart failure during treatment.

Patients should be appropriately anticoagulated as per clinical AF guidelines. International Normalised Ratio (INR) should be closely monitored after initiating dronedarone in patients taking vitamin K antagonists as per the prescribing information for these products.

Hepatic monitoring

Liver-function tests should be done: before starting treatment with dronedarone; after 1 week of treatment; after 1 month of treatment; then every month for 6 months; at month 9; at month 12; and periodically thereafter

Renal monitoring

Plasma creatinine values should be measured before and 7 days after initiation of dronedarone, and renal function should be monitored periodically afterwards. Discontinue treatment in any patients with further elevations of serum creatinine.

Pulmonary monitoring

Cases of interstitial lung disease, including pneumonitis and pulmonary fibrosis, have been reported in association with dronedarone. Onset of dyspnoea or non-productive cough may be related to pulmonary toxicity. If pulmonary toxicity is suspected during treatment, relevant lung examinations should be considered and treatment discontinued if confirmed.

Advice for patients:

  • patients should be advised to make a routine appointment to discuss their treatment with the treating physician, but should not stop taking dronedarone unless told to do so

Report suspected adverse reactions

Please report all suspected adverse reactions to dronedarone via the Yellow Card scheme.

Further information

BNF Treatment Summary for Arrhythmias

Article citation: Drug Safety Update Oct 2011, vol 5 issue 3: A1.

Post-publication note:

In March 2022, links were updated during routine review of older articles

Published 11 December 2014