FDA's announcement it is investigating a possible risk of liver injury related to orlistat - the active ingredient in Roche Pharmaceuticals' prescription weight-loss drug Xenical and GlaxoSmithKline's OTC alli - could threaten short-term sales.

Despite FDA's encouragement that consumers and patients continue to use orlistat as directed, the announcement of the ongoing safety review could taint public perception of the drug.

The agency says in an Aug. 24 "early communication" letter it received 32 reports of serious liver injury in patients taking orlistat - between 1999, when it first approved Xenical (120 mg), and 2008. FDA approved alli (60 mg) in 2007.

FDA first reported on its Web site in June that it was evaluating "rare reports" of hepatitis and liver-related abnormalities in patients taking orlistat. The agency told "The Tan Sheet" it was investigating the adverse events for a possible causal link (¹ 'The Tan Sheet' June 8, 2009, In Brief). Separately, FDA said in February that it was investigating reports of rectal bleeding linked to use of the drug.

Even though FDA emphasizes there is "no definite association between liver injury and orlistat," a spokeswoman said the agency announced the safety review now because "orlistat is a widely used drug, and we wanted to give consumers and health care professionals as much information as possible."

The announcement is "in keeping with FDA's commitment to inform the public about its ongoing safety reviews of drugs," FDA said.

The agency began using early communication letters in 2007 in an attempt to improve transparency. It sent early communication letters about Chantix smoking-cessation products in November 2008, and the proton pump inhibitors Prilosec and Nexium in August 2007 (² 'The Tan Sheet' Feb. 4, 2008 and ³ Also see "FDA To Complete Prilosec, Nexium Safety Review In November, CDER Says" - Pink Sheet, 13 August, 2007.). FDA later said preliminary conclusions of its safety review of Prilosec and Nexium determined no link between the drugs and cardiovascular risks.

The vast majority of the orlistat adverse event reports - 30 - occurred outside of the U.S. and required hospitalization. A total of six cases resulted in liver failure, but most included jaundice, weakness and stomach pain, FDA says.

The spokeswoman added that the two U.S. cases, a liver failure case and a case of severe hepatotoxicity, involved alli.

A GSK spokeswoman acknowledged the reports, but noted they are "a relatively small number," considering more than 6 million people have used alli since it launched. She also emphasized there is no causal relationship between the reports and orlistat.

"Alli is a 'non-systemically' acting medicine - it is minimally absorbed in the blood and works locally in the gastrointestinal tract. There is, therefore, no obvious biological mechanism to explain how liver damage can occur with alli," she said. "Liver changes can have many causes. For example, people who are overweight and obese are predisposed to liver-related disorders," she added.

Still, the FDA spokeswoman said the two U.S. cases, which were first reported in February and May 2008, triggered a "more intensive review of the potential for liver injury."

FDA is updating its analysis of adverse event reports as case reporting continues, the spokeswoman said. The agency also noted it is reviewing additional data from GSK and Roche of suspected liver injury associated with orlistat.

Both firms say they are working with FDA to continually monitor and evaluate adverse effects associated with orlistat and stress that consumer safety is "of utmost importance."

The announcement could further damage alli sales, which fell 53 percent to $139 million in fiscal 2008 after a successful June 2007 launch in the U.S. (⁴ Also see "GSK Upbeat On Alli In EU As Global Consumer Sales Show Healthy Gains" - Pink Sheet, 27 July, 2009.).

Alli sales could fall 10 to 20 percent in the near term, but should recover, said Donald Riker, founder and president of On Point Advisors in Chattanooga, Tenn.

He explained media coverage of the notice is light so far, and it likely will have a "fleeting effect" on alli users, many of whom are loyal and willing to accept the product's high cost and negative side effects, such as anal leakage.

- Elizabeth Crawford ( ⁵ e.crawford@elsevier.com )

FDA Alerts Public To Ongoing Safety Review Of Orlistat In GSK, Roche Drugs

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