Dronedarone hydrochloride


Brand Name(s):Multaq,

Indication:Atrial fibrillation (AF)



Review Date:Jan-25

EMA Guidance
European Medicines Agency recommends restricting use of Multaq
Benefit-risk balance of anti-arrhythmic medicine remains positive in a limited population of patients with paroxysmal or persistent atrial fibrillation
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended restricting the use of Multaq. The anti-arrhythmic medicine should only be prescribed for maintaining heart rhythm in patients with paroxysmal or persistent atrial fibrillation for the maintenance of sinus rhythm after successful cardioversion. Due to an increased risk of liver, lung and cardiovascular adverse events, Multaq should only be prescribed after alternative treatment options have been considered. The Committee also recommended a number of other risk minimisation measures to reduce the risk of injuries to liver, lung and cardiovascular system.
Patients who are currently taking Multaq are recommended to have their treatment evaluated by their doctor at their next scheduled appointment.
Multaq (dronedarone) is an anti-arrhythmic medicine. It was authorised in 2009 for use in adults who have had atrial fibrillation in the past or who currently have non-permanent fibrillation.
The review of the overall balance of benefits and risks of Multaq was initiated in January 2011 because of reports of severe liver injury in patients treated with the medicine. During the review the CHMP was informed of the early termination of a clinical trial, the PALLAS study, due to the occurrence of severe cardiovascular side effects such as cardiovascular death, stroke and cardiovascular hospitalisation in patients taking the medicine. The PALLAS study investigated the use of Multaq compared to placebo in patients over 65 years of age with permanent atrial fibrillation and several risk factors. Although Multaq has not been approved for this patient population, the CHMP was concerned about the outcome of the PALLAS study and extended its review to also look at the data relating to cardiovascular safety of the medicine as well as other data that became available on the risk of damage to the lungs.
On the basis of the evaluation of the currently available data, the Committee concluded that there was an increased risk of Multaq causing injury to the liver as well as the lungs when used in accordance with the currently approved prescribing information. The Committee also considered that the
cardiovascular events shown in the population in the PALLAS study could mean an increased risk of cardiovascular side effects for some patients with non-permanent atrial fibrillation. However, the Committee considered that the availability of a range of treatments for a difficult condition such as atrial fibrillation was important and that for some patients with non-permanent atrial fibrillation Multaq remains a useful treatment option. The CHMP therefore was of the opinion that the benefits of Multaq outweigh its risks in these patients, provided that further changes to the information for prescribers and patients will be introduced to minimise the risk of injury to the liver, lung and heart. These include:
*Treatment with Multaq should be restricted to patients with paroxysmal or persistent atrial fibrillation when sinus rhythm has been obtained. It is no longer indicated for use in patients when atrial fibrillation is still present.
*Treatment with Multaq should only be started and monitored by a specialist after other anti-arrhythmic medicines have been considered.
*Multaq must not be used in patients with permanent atrial fibrillation, heart failure or left ventricular systolic dysfunction (impairment of the left side of the heart).
*Doctors should consider discontinuation of treatment if atrial fibrillation reoccurs.
*Multaq must not be used in patients who have had previous liver or lung injury following treatment with amiodarone, another anti-arrhythmic medicine.
*Patients on Multaq should have their lung and liver function as well as their heart rhythm regularly monitored. Especially the liver function should be closely monitored during the first few weeks of treatment.

The Committee’s opinion has now been forwarded to the European Commission for the adoption of a decision.

EMA Press release 22/09/2011

Dronedarone: risk of cardiac failure and risk of hepatotoxicity
MHRA Drug safety update Volume 4 Issue 7 February 2011

Current Guidance:

– Cases of liver injury, including two cases of liver failure requiring transplantation have been reported in patients receiving dronedarone. Some of these cases have occurred early after starting treatment.

– For patients prescribed dronedarone, liver function tests should be performed:
– prior to treatment,
– on a monthly basis for 6 months,
– at months 9 and 12, and periodically thereafter.

– Patients currently receiving dronedarone should be contacted within the next month so that liver function tests could be performed and thereafter they should be tested as listed above depending on when treatment was initiated.

– If alanine transaminase (ALT) levels are elevated to 3 or more upper limit of normal (ULN), levels should be re-measured within 48 to 72 hours. If ALT levels are confirmed to be 3 or more ULN after re-measurement, dronedarone treatment should be withdrawn.

– Patients should be advised to contact health care professionals immediately in case of signs or symptoms of liver injury.

Information on severe liver injury associated with the use of Multaq (dronedarone)
Sanofi aventis 19th January 2011

1.1 Dronedarone is recommended as an option for the treatment of non-permanent atrial fibrillation only in people:
whose atrial fibrillation is not controlled by first-line therapy (usually including beta-blockers), that is, as a second-line treatment option, and
who have at least one of the following cardiovascular risk factors:
* hypertension requiring drugs of at least two different classes
* diabetes mellitus
* previous transient ischaemic attack, stroke or systemic embolism
* left atrial diameter of 50 mm or greater
* left ventricular ejection fraction less than 40% (noting that the summary of product characteristics [SPC] does not recommend dronedarone for people with left ventricular ejection fraction less than 35% because of limited experience of using it in this group) or
age 70 years or older, and
* who do not have unstable New York Heart Association (NYHA) class III or IV heart failure.

1.2 People who do not meet the criteria in section 1.1 who are currently receiving dronedarone should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

Dronedarone for the treatment of non-permanent atrial fibrillation August 2010