NPC Archive Item: EMA recommends restricting the use of dronedarone▼

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29 September 2011

Following a review of its benefit-risk balance, the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended that dronedarone▼ should only be prescribed for the maintenance of heart rhythm in patients with paroxysmal or persistent atrial fibrillation (AF) and whose normal rhythm has been restored. It should not be used in patients with permanent AF, heart failure or left ventricular systolic dysfunction. Due to an increased risk of liver, lung and CV adverse events, dronedarone should only be prescribed after alternative treatment options have been considered.

Healthcare professionals involved in managing patients with AF should familiarise themselves with the changes to the prescribing information (see below), which are being introduced to minimise the risk of liver, lung and cardiovascular (CV) adverse events. Furthermore, patients should have their dronedarone treatment evaluated at their next scheduled appointment.

Summary of changes to the prescribing information for dronedarone

  • Treatment with dronedarone 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 in whom AF is still present.
  • Dronedarone should only be prescribed if other anti-arrhythmic medicines have been considered.
  • Treatment with dronedarone should only be started and monitored by a specialist.
  • Dronedarone must not be used in patients with permanent AF, heart failure or left ventricular systolic dysfunction.
  • Prescribers should consider discontinuing treatment if AF reoccurs.
  • Switching treatment from amiodarone to dronedarone should be done cautiously by a specialist.
  • Dronedarone must not be used in patients who have had previous liver or lung injury following treatment with amiodarone.
  • Patients on dronedarone should have their lung and liver function as well as their heart rhythm regularly monitored. Liver function should be monitored especially closely during the first few weeks. Kidney function should also be monitored during the first week of treatment.

What is the background to this?
Dronedarone is currently indicated in clinically stable adults with a history of, or current non-permanent AF.

The CHMP began to review the overall balance of benefits and risks of dronedarone in January 2011 following reports of severe liver injury. They recommended that changes should be made to the prescribing information for dronedarone to ensure that patients’ liver function is tested before initiation of treatment, closely monitored during treatment, and treatment is stopped if there are signs of potential liver damage (see On the Horizon Rapid Review No. 2429).

The MHRA reported that dronedarone may also be associated with an elevated risk of worsening, or new-onset, heart failure. February Drug Safety Update advised that patients should be asked to be vigilant for the symptoms of heart failure or liver toxicity during treatment, and should undergo regular liver-function testing

During their review, the CHMP was informed of the early termination of the PALLAS study due to an increased risk of severe CV adverse effects (e.g. CV death, stroke and CV hospitalisation) in patients with permanent AF who were taking dronedarone. Although dronedarone has not been approved for this indication, the CHMP extended its review to look at the data relating to its CV safety (see MeReC Rapid Review No. 4090), as well as other data that became available on the risk of damage to the lungs.

What did the review conclude?
The CHMP concluded that dronedarone increases the risk of liver and lung damage when used in accordance with the currently approved prescribing information. In addition, although the population in the PALLAS study (permanent AF with several risk factors) differs from the currently approved population (non-permanent AF), the increased risk of CV adverse effects seen in this study could be relevant for some patients with non-permanent AF.

The CHMP considered that dronedarone remains an important treatment option for some patients with non-permanent AF and was of the opinion that the benefits outweigh the risks in these patients, provided that a number of measures are taken to minimise the risk of injury to the liver, lung and heart. Importantly, patients who are currently taking dronedarone are recommended to have their treatment evaluated by their doctor at their next scheduled appointment, and to speak to their doctor or pharmacist if they have any questions. More information is available in Questions and answers on the review of dronedarone.

The CHMP and the manufacturer of dronedarone have agreed on a letter to be sent out shortly to prescribers in the EU explaining the changes to the prescribing information. The Committee’s opinion has now been forwarded to the European Commission for the adoption of a decision.

What does NICE say about dronedarone?
As we highlighted in MeReC Rapid Review No. 1840, NICE technology appraisal 127 recommends dronedarone as an option for the treatment of non-permanent AF for new patients only in people who meet all of the following criteria:

  • Their AF is not controlled by first-line therapy (usually including beta-blockers)
  • They do not have unstable NYHA class III or IV heart failure
  • They have at least one of the following CV risk factors:
    • Hypertension being treated with at least two different classes of drugs
    • 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%
    • Age 70 years or older.

Healthcare professionals should follow the NICE guideline taking into account the additional recommendations from the EMA.

Further information can be found on NHS Evidence and in the Cardiovascular – atrial fibrillation elearning section of the NPC website.

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