Patients who are currently taking Multaq are recommended to have their treatment evaluated by their doctor at their next scheduled appointment.

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 AF 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 AF.

However, the Committee considered that the availability of a range of treatments for a difficult condition such as AF was important and that for some patients with non-permanent AF 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 AF when sinus rhythm has been obtained. It is no longer indicated for use in patients when AF 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 AF, heart failure or left ventricular systolic dysfunction (impairment of the left side of the heart).

- Doctors should consider discontinuation of treatment if AF 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.

Dr Derick Todd, Consultant Electrophysiologist at The Liverpool Heart and Chest Hospital, says: “The treatment of AF is about making patients feel better and protecting them from the negative health outcomes associated with AF.  I am excited that dronedarone (Multaq®) is now available, which is a valuable additional choice for the treatment of AF.  For the first time I will feel that a drug I use to treat AF will also reduce the morbidity associated with AF such as hospitalisation, stroke and cardiovascular mortality.”

Indicated in adult clinically stable patients with a history of, or current non permanent atrial fibrillation (AF) to prevent recurrence of AF or lower ventricular rate  dronedarone is the first heart rhythm drug shown in clinical studies not only to maintain normal heart rhythm and reduce ventricular rate, but also to help keep patients out of hospital and to reduce the risk of death due to cardiova scular-related causes, compared to placebo, in addition to standard therapy.

Trudie Lobban, Founder and Chief Executive Officer of the Atrial Fibrillation Association said “The availability of a new treatment for AF is very welcome news for patients with this potentially life-limiting condition. AF affects the quality of life of both patients and their families and it has been a long time since we’ve seen new therapies in this area, giving hope to thousands who are struggling with this debilitating condition.”

This patient population corresponds to the patients included in the ATHENA study ¹, the largest study ever performed with an anti-arrhythmic drug in atrial fibrillation and the only study to have ever demonstrated a positive impact on cardiovascular (CV) morbidity and mortality.

In ATHENA, dronedarone reduced the risk of cardiovascular hospitalization or death by a significant 24% vs. placebo on top of standard of care including beta-blockers (p<0.001) with no difference in the rate of serious adverse events (19.9% vs 21.1% respectively; p = 0.31).

The Arrhythmia Alliance welcomed the decision by NICE to recommend approval of dronedarone as a second line treatment option for Atrial Fibrillation (AF) patients, reversing its previous draft guidance.

NICE’s Appraisal Committee recognised that dronedarone can and should occupy a currently vaca(2nt place in the care pathway, and that for a large and growing number of patients it could represent the only treatment option open to them.

Trudie Lobban, CEO of the Atrial Fibrillation Association which is campaigning for dronedarone to be approved said: “For thousands of AF patients this news will give them new hope that they will be able to lead a fulfilled and productive life. NICE’s decision is triumph of common sense and will restore patient and healthcare professionals faith in NICE processes and evidence hearing. They took into account the value of the drug to patients whose lives have been crippled with either the symptoms of AF or the side effects of other treatments.  It is important that symptomatic AF patients have access to specialist consultants who will be aware of the benefits of this new drug.

“I would like to thank all the patients, carers and clinicians who took the time to respond to the earlier Appraisal Consultation Document by NICE which ensured that a review was held and evidence from leading arrhythmia clinicians and AF patients was heard. Without their support many thousands of AF sufferers would be left without hope.”

Professor John Camm, Head of the Department of Cardiac & Vascular Sciences at St George’s, University of London, a Trustee of AFA and President of Arrhythmia Alliance said: “This decision will please many clinicians working in our field. It enables us to have the authority to prescribe dronedarone and gives us an additional treatment for patients who may have run out of options. I want to thank the NICE committee for being so responsive to requests to review all the evidence.”

Multaq® will be commercially available in the UK from Tuesday, March 30, 2010.

Multaq® has a fixed dose regimen of twice daily 400 mg tablets to be taken with morning and evening meals. Treatment with Multaq® does not require a loading dose and can be initiated in an outpatient setting. Most common adverse reactions are diarrhea, nausea, vomiting, abdominal pain, asthenia (weakness) and skin rash.

The European Commission granted marketing authorization for Multaq® in November 2009. Multaq® is indicated in the EU in adult clinically stable patients with a history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate. ² The use of Multaq® in unstable patients with NYHA class III and IV heart failure is contraindicated. Because of limited experience in stable patients with recent (1 to 3 months) NYHA class III heart failure or with Left Ventricular Ejection Fraction (LVEF) <35%, the use of Multaq® is not recommended in these patients.

Multaq® is currently available in the U.S., Canada, Switzerland, Germany, Denmark, Ireland, Norway and Finland and is being launched in most European countries in 2010.

The NICE process for Multaq®

• The stakeholder consultation period for this ACD closes on 22 April
• Stakeholder comments submitted to NICE on this ACD will be considered at the Appraisal Committee Meeting on 26 May
• If a Final Appraisal Determination (FAD) is produced following the Appraisal Committee Meeting it would be expected in early July
• If the FAD is not appealed, publication of Final Guidance would be expected sometime between July and September.

1. This new appraisal document is not the final NICE guidance on Multaq®.  A consultation period is ongoing until April 22nd, 2010. The appraisal committee will meet again to consider the evidence on May 26, 2010. After this meeting the Committee will prepare the final appraisal determination (FAD) for Multaq®.

References

1. Hohnloser S.H, Crijns H.J.G.M., van Eickels M, et al. Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation, N Engl J Med 2009; 360:668-78.
2. European Medicines Agency. European Public Assessment Report.  Doc. Ref.: EMA/625172/2009; EMEA/H/C/1043

In the Summary of Positive Opinion, the CHMP has acknowledged that dronedarone has been shown,  in addition to its rhythm and rate controlling properties, to decrease the risk of atrial fibrillation-related hospitalisations.

The positive opinion from the CHMP needs now to be ratified by the European Commission.

“Sanofi-aventis welcomes the positive CHMP recommendation for the approval of Multaq® in the European Union” said Jean-Pierre Lehner, Chief Medical Officer, sanofi-aventis. “This decision brings new hope to people whose lives are impacted by the potential cardiovascular complications of atrial fibrillation. We do think that Multaq^® will contribute to fulfill significant unmet medical needs for the patients”.

The CHMP positive opinion is based on the submission of a comprehensive clinical data package including seven international, multi-center, randomized clinical trials involving more than 7000 patients and including the landmark ATHENA trial.

The ATHENA trial involved 4,628 patients with Atrial Fibrillation / Atrial Futter or a recent history of these conditions and showed that Multaq^® (dronedarone) in addition to standard therapy, reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24% (p<0.001) when compared to placebo, meeting the study’s primary endpoint. Reported significant adverse events in the Multaq^® arm included diarrhoea, nausea, bradycardia, QT-interval prolongation and cutaneous rash.

The incidence of atrial fibrillation is growing worldwide in relation to aging populations. It is emerging as a public health concern and affects about 4.5 million people and represents one-third of hospitalizations for arrhythmia in the European Union. Atrial fibrillation leads to potential life-threatening complications. AF increases the risk of stroke up to five-fold , worsens the prognosis of patients with cardiovascular risk factors, and doubles the risk of mortality with significant burden on patients, health care providers and payers.

Multaq® has recently received approval from the U.S. Food and Drug Administration (FDA), Health Canada and Swissmedic (Swiss Health Authority).

Dronaderone is an anti-arrhythmic indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors, who are in sinus rhythm or who will be cardioverted. Associated cardiovascular risk factors include age over 70 years, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%. The FDA approval is based on five international, multi-center, randomized clinical trials involving nearly 6,300 patients.

The landmark ATHENA trial evaluated the efficacy and safety of dronaderone in patients with AF/AFL or a recent history of these conditions (71% of these patients had no heart failure, 29% were in NYHA class I-III with stable heart failure). This trial showed that dronedarone 400 mg BID, in addition to standard therapy, by 24% (p<0.001) when compared to placebo, meeting the study’s primary endpoint.

This reduction was generally consistent across study subgroups based on baseline characteristics or medications. Patients taking dronaderone had higher rates of diarrhoea, nausea, bradycardia, QT-interval prolongation and cutaneous rash than patients taking placebo.

Initiation of dronaderone treatment is contraindicated in patients with severe heart failure (NYHA class IV) or NYHA Class II – III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. This unstable population corresponds to the population of the ANDROMEDA trial in which patients receiving dronedarone had a greater than 2-fold increase in mortality compared to placebo.

The ATHENA and ANDROMEDA trials provided two sets of data supporting the assessment of the product’s benefit risk ratio in two significantly different patient populations.

To ensure the use of dronaderone in the appropriate patient population, the manufacturers, sanofi-aventis U.S. LLC also announced the launch of mPACT™ – Multaq^® Partnership for Appropriate Care and Treatment-the Risk Evaluation and Mitigation Strategy (REMS) developed by sanofi-aventis US.LLC. The mPACT™ Partnership was developed to assist health care professionals (HCPs) with the identification of appropriate patients and to ensure the safe use of Multaq while minimizing risk. The risk mitigation programme consists of a Communication plan for HCP, a medication plan for patients and post-marketing surveillance.

A registration dossier of Multaq^® is also under regulatory review by the European Medicines Agency (EMEA).

For full prescribing information, please visit http://products.sanofi-aventis.us/Multaq/Multaq.pdf