Dronedarone (Multaq®) and severe hepatic injury

HSA is alerting healthcare professionals to overseas cases of rare, but severe liver injury, including two cases of acute liver failure leading to liver transplant in patients treated with dronedarone.

Dronedarone (Multaq®, Sanofi-Aventis Singapore Pte Ltd), an anti-arrhythmic, has been licensed locally since August 2010. It is indicated to prevent recurrence of atrial fibrillation (AF) or to lower ventricular rate in clinically stable adult patients with a history of AF, or with current non-permanent AF.

Acute hepatic failure requiring transplantation

HSA was informed of several overseas case reports of hepatocellular liver injury and liver failure in patients treated with dronedarone. There were two cases of liver failure that required liver transplantation that occurred in October and November 2010. Both patients were females, aged 69 and 72 years old and their explanted livers showed evidence of extensive hepatocellular necrosis.

The first patient who underwent liver transplant had underlying intermittent AF, arterial hypertension and stable coronary artery disease. She was taking dronedarone for a total of 4.5 months. Two weeks prior to hospitalisation, she experienced increased exhaustion and tiredness. A week prior to admission, dronedarone was discontinued and at the time of admission, the patient was noted to have jaundice, coagulopathy, transaminitis and hyperbilirubinaemia, which progressed to hepatic encephalopathy over the next nine days. Liver transplantation was performed after all other causes concerning liver damage had been excluded.

The second patient had a medical history of paroxysmal AF and SjÖgren's syndrome. Six months following initiation of dronedarone, the patient developed weakness, abdominal pain, coagulopathy, transaminitis and hyperbilirubinaemia. Liver tests and transplant work-up performed did not reveal any alternative causes of liver damage and liver transplantation was performed successfully.

Although both patients were taking concomitant medications such as anti-hypertensives (eg, amlodipine), cholesterol-lowering medications (eg, simvastatin) and anticoagulants (eg, warfarin), a causal relationship with dronedarone could not be excluded.

International regulatory actions

On 14 January 2011, the US FDA1 issued a drug safety communication to alert healthcare professionals and patients about reports of rare, but severe liver injury, including the two cases of liver transplant in patients treated with dronedarone. Information about the potential risk of liver injury was added to the “Warnings and Precautions” and “Adverse Reactions” sections of the dronedarone package inserts (PI).

Similar regulatory actions were also taken by the European Medicines Agency2 and Health Canada3 where the PI for Multaq® has been strengthened to include warnings of liver injury.

Local regulatory actions

To date, HSA has not received any local reports of liver injuries associated with dronedarone. A Dear Healthcare Professional Letter4,5 has been issued on 8 June 2011 to inform healthcare professionals of liver injuries reported in patients treated with dronedarone. The local PI and physician educational materials for Multaq® have also been updated to include warnings on the risk of liver injury.

Healthcare professionals are advised to counsel their patients to look out for signs and symptoms of liver injury or toxicity such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching and to periodically monitor serum liver enzymes and bilirubin in patients taking dronedarone.

Healthcare professionals are also encouraged to refer to the latest prescribing information in the PI6 of Multaq® when prescribing the drug to patients and to report any liver-related adverse reactions associated with the use of dronedarone to the Vigilance Branch of HSA.

References

  1. FDA Drug Safety Communication: Severe liver injury associated with the use of dronedarone.
    http://www.fda.gov/Drugs/DrugSafety/ucm240011.htm
  2. European Medicines Agency: Benefit-risk review of Multaq started
    http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/01/news_detail_001187.jsp&mid=WC0b01ac058004d5c1
  3. Updated Safety Information for Multaq® (dronedarone) in regards to hepatocellular liver injury.
    http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2011/14651a-eng.php
  4. HSA website. Dear Healthcare Professional Letters (DHCPL).
    https://www-hsa-gov-sg.cwp.sg/announcements/Dear-Healthcare-Professional-Letters
  5. MOH-Health Professionals Portal.
    http://www.hpp.moh.gov.sg
  6. HSA website. Inforsearch for Singapore package inserts
Healthcare professional, Industry member, Therapeutic Products
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