Orlistat and post-marketing reports of severe liver injury

The HSA's Vigilance Branch would like to update healthcare professionals on the post-marketing reports of liver injuries associated with the use of orlistat. Orlistat is a potent inhibitor of gastrointestinal lipases thereby reducing the ingested dietary fat absorption and total energy intake to produce weight loss.

Orlistat is registered in Singapore under the trade names of Alli® (GSK) and Xenical® (Roche). Xenical® has been registered locally since 1999 and is indicated for the treatment of obese patients with a body mass index (BMI) ≥30 kg/m², or overweight patients (BMI ≥ 28 kg/m²) with associated risk factors, in conjunction with a mildly hypocaloric diet. Alli® has been licensed for use locally in 2010, with the same indication as Xenical, and it is to be used in adults aged 18 years and over, along with a reduced-calorie and low-fat diet.

Reviews performed by drug agencies to date

US

The US Food and Drug Administration (FDA) has completed its review of the reports of serious liver injuries associated with the use of Xenical® and Alli®.¹ The agency had identified a total of 13 reports of severe liver injury associated with the use of these orlistat-containing medicines: 12 foreign reports with Xenical® and one U.S. report with Alli®. Of these 13 cases, two patients died from liver failure while three patients required liver transplantation. The FDA reported that a causal relationship between severe liver injury and the use of orlistat has not been established. This causality link was difficult to establish as these reports of severe liver injury had occurred over a period of 10 years, during which an estimated 40 million people worldwide could have consumed orlistat. Some of the patients in the reported cases had also taken other medications or had other medical conditions that may have contributed to the development of severe liver injury.

The FDA has included information regarding the cases of severe liver injury to the label of Xenical® and Alli®. This is to increase the awareness among the healthcare professionals on these post-marketing cases of severe liver injury associated with the use of orlistat and to educate patients using these medicines about the signs and symptoms of liver injury.

Europe

A Europe-wide review on the possible association between serious hepatic reactions and orlistat use was conducted in July 2009.² The data that was reviewed included non-clinical, clinical trial, post-marketing safety data provided by the product licence holders and suspected adverse reaction reports submitted to the UK Medicines and Healthcare products Regulatory Agency. The European review concluded that there was insufficient evidence to show that either Xenical® or Alli® were associated with more serious liver disorders than those currently listed in the product information (such as hepatitis, cholelithiasis, increased transaminases) and no further regulatory action was recommended.

Singapore

In August 2009, the Vigilance Branch, HSA undertook a safety review of the cases of hepatic disorders associated with the use of Xenical® that were submitted to the FDA. It was found that over 50% of these drug-induced hepatic reports were confounded by the use of concurrent medicines (e.g. alcohol, paracetamol, statins) or underlying medical conditions such as obesity and gallstones.

Local cases

Since 2000, HSA has received two local reports of liver toxicities suspected to be associated with the use of orlistat. The first case was reported in 2000, which described a case of jaundice and fulminant liver failure with massive hepatocellular necrosis in a 62 year-old man.³ However, the causality of liver failure was unclear as the patient was also taking paracetamol. A second case was reported in 2002, whereby the patient was reported to have elevated liver enzymes.

HSA's advisory

The local patient information leaflets and package inserts of both Xenical®and Alli® currently carry warnings on the possible risk of hepatic-related adverse effects associated with the use of these medicines.

In view of the potential for rare but severe liver injuries, it is recommended that healthcare professionals consider the benefits and risks associated with the use of orlistat before prescribing or recommending these medications to their patients. Healthcare professionals are advised to inform their patients to stop the use of orlistat and seek medical attention immediately if they experience symptoms that may be possibly associated with liver injury, such as fever, jaundice, or brown urine. Healthcare professionals are encouraged to report any adverse drug reactions that are suspected to be associated with the use of orlistat to the Vigilance Branch of HSA.

References

1. FDA Drug Safety Communication
   http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213038.htm

2. MHRA Drug Safety Update: Volume 3, Issue 7, February 2010
   http://www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON071085

3. Med Sci Law 2002, 42: 309-12