Multaq

Multaq can only be obtained with a prescription and treatment with it should be started and monitored under specialist supervision.

Multaq is available as tablets (400 mg) and the recommended dose is one tablet twice a day, with the morning and evening meals.

The active substance in Multaq, dronedarone, works mainly by blocking channels through which charged particles of potassium flow in and out of the heart muscle cells. Increased flow of charged particles produces the excessive electrical activity that leads to atrial fibrillation and rapid heart rate. By reducing the flow of potassium through the channels, Multaq slows down contractions in the atria and so prevents fibrillation and lowers the heart rate.

There were six main studies of Multaq in adults who had had atrial fibrillation.

The first three studies, involving, 1,411 patients, found that Multaq was more effective than placebo (a dummy treatment) at preventing atrial fibrillation. The main measure of effectiveness was how long the treatment prevented an attack of atrial fibrillation or the change in the patients’ heart rate after two weeks. Multaq prevented fibrillation for an average of 116 days compared to 53 days with placebo. Heart rate was reduced by an average of 11.0 beats per minute in patients taking Multaq compared to 0.7 beats per minute in patients taking placebo.

The fourth study compared Multaq with amiodarone (another medicine used to prevent atrial fibrillation) in 504 patients. Multaq was less effective than amiodarone at maintaining normal rhythm: after a year, atrial fibrillation came back or treatment was stopped in 75% of the patients taking Multaq, compared with 59% of the patients receiving amiodarone. However, more patients taking amiodarone had to stop treatment because of side effects.

The fifth study compared Multaq with placebo in almost 5,000 patients. It gave further support for the use of Multaq to maintain normal heart rhythm and to reduce the heart rate. The study found that in patients taking Multaq, there were fewer hospital admissions for cardiovascular disorders (problems affecting the heart and blood vessels), particularly those related to atrial fibrillations.

A sixth study (PALLAS) compared Multaq with placebo in patients over 65 years of age with permanent atrial fibrillation and several risk factors. The study was stopped early because of severe cardiovascular events (such as cardiovascular death or hospitalisation and stroke) in some patients taking Multaq.

The most common side effects with Multaq (seen in more than 1 patient in 10) are increased blood levels of creatinine (a breakdown product of muscle), a prolonged ‘QTc Bazett’ (an alteration of the electrical activity of the heart) and congestive heart failure (a type of heart disease), but this side effect occurred at a similar rate in patients who took placebo in clinical studies. For the full list of all side effects reported with Multaq, see the package leaflet.

Multaq must not be taken with medicines that can cause torsades de pointes (a type of rapid heart beat), or with dabigatran (a medicine to prevent blood clotting). It must not be used in patients with permanent atrial fibrillation of unknown duration or lasting for more than six months when the doctor has decided not to try to restore normal rhythm. It must also not be used in patients with some other heart problems, such as some problems with the electrical activity, very slow heart beats or heart failure.

Multaq must not be used in patients who have severe problems with their liver or kidneys. Patients who have had previous liver or lung injury following treatment with amiodarone (another anti-arrhythmic medicine) must not be given Multaq. For the full list of restrictions, see the package leaflet.

The European Commission granted a marketing authorisation valid throughout the European Union for Multaq on 26 November 2009.

The company that makes Multaq must ensure that healthcare professionals who prescribe and dispense the medicine in all Member States are given a ‘prescriber guide’. The prescriber guide will help healthcare professionals to use Multaq safety and to select patients for whom it is appropriate. The guide will also include information on: when not to use Multaq; medicines that interact with Multaq; the need to monitor the function of the liver, lung, heart and kidneys before and during treatment; and what advice to give to patients on Multaq treatment.

Recommendations and precautions to be followed by healthcare professionals and patients for the safe and effective use of Multaq have also been included in the summary of product characteristics and the package leaflet.

Based on the available evidence, the CHMP decided that Multaq’s benefits are greater than its risks and recommended that Multaq be given marketing authorisation.

Multaq was originally approved to prevent atrial fibrillation from coming back or to lower the heart rate in adults who have had or have non-permanent atrial fibrillation. In September 2011 this indication was restricted to the maintenance of normal heart rhythm in ‘persistent’ or ‘paroxysmal’ atrial fibrillation after normal heart rhythm has been restored. This followed a review of data that became available since its authorisation including data from the PALLAS study.1

1In the context of a procedure under Article 20 of Regulation (EC) No 726/2004.

Multaq is an antiarrhythmic medicine used to maintain normal heart rhythm in adults whose normal heart rhythm has been restored after a period of paroxysmal or persistent atrial fibrillation. Atrial fibrillation is when the atria (the upper chambers of the heart) contract irregularly and rapidly, and this abnormality can be short-lasting (paroxysmal) or it can last longer than a few days (persistent).

Multaq should only be prescribed after alternative treatment options have been considered.

Multaq should not be given to patients with left ventricular systolic dysfunction (a problem affecting the left side of the heart) or patients who have or have had heart failure (when the heart cannot pump enough blood around the body). Multaq contains the active substance dronedarone.

MULTAQ is a medicine that consists of tablets containing 400 mg of dronedarone.

MULTAQ was to be used to treat patients with atrial fibrillation or atrial flutter. Atrial fibrillation and atrial flutter are caused by problems in the conduction of electrical impulses in the upper chambers of the heart (atria). Both illnesses cause a rapid heart rate, but atrial fibrillation also makes the heart rhythm irregular.

Atrial fibrillation and flutter are very common conditions, particularly in people over 65 years of age. MULTAQ was expected to help patients maintain normal heart rhythm and to reduce the heart rate.

The active substance in MULTAQ, dronedarone, is an anti-arrhythmic agent. It is expected to correct altered heartbeat by affecting the electrical activity of the heart muscle. The medicine has a number of effects on the heart muscle, including reducing the flow of potassium ions (charged particles) out of the heart cells.

The effects of MULTAQ were first tested in experimental models before being studied in humans. The company presented the results of two clinical trials comparing the effects of MULTAQ and placebo (a dummy treatment) on the maintenance of normal heart rhythm. The studies involved a total of 1,237 patients with an average age above 60 years. All of the patients had had atrial fibrillation or flutter at least once in the past three months but had a normal heart rhythm at the start of the study. The studies examined how long it took for atrial fibrillation or flutter to return.

The company also presented the results of a third study that compared the effects of MULTAQ and placebo on the heart rate in 174 patients who had had atrial fibrillation continuously for over six months. The study measured the change in heart rate between the start of the study and day 14 of treatment. The patients' heart rates were measured when they were resting.

The application was at day 174 when the company withdrew. After the CHMP had assessed the responses from the company to a list of questions, there were still some unresolved issues outstanding. The CHMP normally takes up to 210 days to evaluate a new application. Based on the review of the initial documentation, the CHMP prepares a list of questions at day 120, which is sent to the company. Once the company has supplied responses to the questions, the CHMP reviews them and may, before giving an opinion, ask any remaining questions at day 180. Following a CHMP opinion, it usually takes around 2 months for the European Commission to grant a licence.

Based on the review of the data and the company's response to the CHMP's list of questions at the time of the withdrawal, the CHMP had concerns and was of the provisional opinion that MULTAQ could not be approved for the treatment of atrial fibrillation or atrial flutter.

The CHMP was concerned that the studies presented by the company had not sufficiently shown that MULTAQ's effects on heart rate and rhythm would be beneficial to patients, since they had not compared MULTAQ to an existing medicine licensed for the same conditions. According to their guidelines for medicines used to correct heart rhythm, the CHMP would need to assess the results of a trial comparing MULTAQ to an existing medicine before it can be granted a licence.

The CHMP was also concerned that the levels of MULTAQ could be altered in patients taking some other medicines, including medicines used to treat the heart. In addition, MULTAQ can alter the levels of some other medicines. The CHMP also had concerns over a higher rate of side effects in patients taking MULTAQ than those taking placebo.

Therefore, at the time of the withdrawal, the CHMP's view was that further studies were needed to adequately assess the medicine's benefits and risks.

The letter from the company notifying the EMEA of the withdrawal of the application is available under the tab 'All documents'.

The Company has informed the CHMP that there are no consequences for patients currently included in clinical trials with MULTAQ. If you are in a clinical trial and need more information about your treatment, contact the doctor who is giving it to you.