The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended new restriction on dronedarone (Multaq), Sanofi’s embattled and controversial antiarrhythmic drug. CHMP says that dronedarone should only be used for maintaining sinus rhythm in patients with paroxysmal or persistent AF after successful cardioversion. CHMP said that it was recommending that dronedarone no longer be used in patients who still have AF.
Because the drug increases the risk of liver, lung and cardiovascular adverse events, CHMP recommends that dronedarone should be used only after alternative treatments have been considered. People already taking dronedarone should “have their treatment evaluated by their doctor at their next scheduled appointment.”
CHMP and the FDA began their reviews of dronedarone in January of this year after receiving reports of severe liver injury in people taking the drug, as first publicly reported by CardioBrief (here and here). The review was broadened in July when the PALLAS trial of dronedarone for the treatment of permanent AF was terminated early due to a significant increase in cardiovascular events in the dronedarone arm of the trial.
In its review, CHMP concluded that dronedarone increases the risk of injury to the liver and the lungs and may increase the risk of cardiovascular side effects in some patients with non-permanent AF. However, CHMP affirmed that for some patients with non-permanent AF the drug “remains a useful treatment option” and that its benefits outweigh its risks in these patients.
CHMP also recommended that:
- Dronedarone should only be prescribed by a specialist after other antiarrhythmic agents have been considered.
- Dronedarone should not be used in patients with permanent AF, heart failure, or left ventricular systolic dysfunction.
- Doctors consider discontinuation of dronedarone if atrial fibrillation reoccurs.
- Dronedarone must not be used in patients who have had previous liver or lung injury associated with treatment with amiodarone.
- Patients receiving dronedarone should have regular tests to monitor lung and liver function.
The FDA told CardioBrief that it is continuing its review of the safety of dronedarone and that it hopes “to soon update the public with more information.”
In an article about dronedarone in the Wall Street Journal, several cardiologists had harsh words about dronedarone. Sanjay Kaul said the drug is “not even safe in intermediate-risk patients” and Steve Nissen said he thought the drug is “dangerous.” Electrophysiologist John Mandrola said the drug “just doesn’t work.” Sanofi’s CEO told the Journal that “the company has had ‘positive’ discussions with regulators.”
Here is the EMA press release:
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.
- Multaq has been authorised in the European Union since 26 November 2009 and is marketed in Austria, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Ireland, Italy, Lithuania, Malta, Poland, Slovakia, Slovenia, Spain, Sweden and the United Kingdom, as well as in Iceland and Norway.
- During the assessment the CHMP also received advice from the Scientific Advisory Group on Cardiovascular Issues. This group includes experts in the treatment of cardiovascular diseases and patient representatives More information is available here.
- All other opinions and documents adopted by the CHMP at their September 2011 plenary meeting will be published on Friday, 23 September 2011 at 12.00 noon UK time on a dedicated web page.