FDA panel backs OTC orlistat, with some concern: the advisory panel was troubled about the drug's interactions with warfarin and cyclosporine

OB/GYN News, Feb 15, 2006 by Elizabeth Mechcatie

BETHESDA, MD. -- The advisory panel that gave near-unanimous support for making orlistat available without a prescription also voiced several concerns about the drug's potential for interactions with cyclosporine and warfarin, its limited efficacy in mildly overweight people, and its effectiveness for maintaining weight loss after 6 months of use.

At a joint meeting of the Food and Drug Administration's nonprescription drugs advisory committee and the endocrinologic and metabolic drugs advisory committee last month, panel members voted 11-3 in favor of making 60-mg capsules available over the counter for weight loss.

GlaxoSmithKline Inc. (GSK) is proposing that orlistat be approved for promoting weight loss in conjunction with a reduced-calorie and low-fat diet in overweight people. The recommended dose would be one to two capsules three times a day with meals for a treatment duration of up to 6 months.

Orlistat, a nonsystemic drug that works locally in the GI tract to prevent absorption of up to 30% of dietary fat, has no effects on the central nervous system, is not addictive, and has no harmful cardiovascular effects. Gastrointestinal side effects include oily spotting, fecal incontinence, fecal urgency, and oily stools.

Since 1999, 120-mg orlistat capsules have been available by prescription as Xenical in the United States. The recommended prescription dose is 120 mg three times a day for people who are obese. The 120-mg capsules will continue to be available by prescription for managing obesity and for patients who should be treated by a physician, according to GSK Consumer Health Care.

If approved for over-the-counter (OTC) use, the 60-mg capsule will be marketed as Alli (pronounced ally), and will be the first medication for weight loss to be approved for nonprescription use. Other OTC products promoted for weight loss are regulated as dietary supplements.

Orlistat has been studied in more than 100 clinical trials involving a total of 30,000 patients, with data on up to 4 years of treatment and has been used in 22 million people, according to GSK. In support of the OTC approval, the company provided data from three clinical trials where the 60-mg dose was tested over 4-6 months, a label comprehension study, and an "actual use" study.

In the three studies of 1,729 people with a body mass index (BMI) of 25-43 kg/[m.sup.2] (ranging from mildly overweight to obese), significantly more of those taking 60 mg three times a day lost at least 5% of their body weight, compared with those on placebo. Completion rates in the studies ranged from 72%-76% among those on placebo to 78%-82% among those on 60 mg of orlistat.

In the two 6-month studies of people with BMIs ranging from 28 to 43 kg/[m.sup.2], 38%-55% of those on orlistat lost at least 5% of their body weight, compared with 21%-31% of those on placebo. In one study, orlistat users lost a mean of about 12 pounds and placebo users lost 7 pounds; in a second study, orlistat users lost about 8 pounds and placebo users lost about 2 pounds. In these studies, nearly 20% of subjects on 60 mg three times a day had experienced fecal urgency, oily spotting, or flatus with discharge.

In the third study of nearly 400 mildly overweight patients, more people on orlistat lost at least 5% of their body weight, compared with placebo users. But the mean weight lost among those on orlistat was about 2.4 pounds.

Supporting approval, panel chair Dr. Alastair Wood, professor of medicine and pharmacology, Vanderbilt University, Nashville, Tenn., said that "the risks seem relatively small." Orlistat's various GI side effects should be clearly outlined to consumers, he said, because they are real risks with "all sorts of social consequences."

Also voting for approval, Dr. Morris Schambelan, chief of the division of endocrinology, University of San Francisco, said that despite some concerns, orlistat is not systemic and does not have CNS effects.

Potential benefits cited for OTC availability included the possibility that consumers might be less likely to use OTC products promoted for weight loss, such as those that contain caffeine.

Voting against approval, Dr. Ruth Parker, of Emory University School of Medicine, Atlanta, said, "I would advise patients to use their limited resources" toward diet and exercise.

"If I were to vote yes, it would be because I would be glad that [purchasers] would be getting the kit that encouraged these other activities more than the pharmacologic impact of the pill." Dr. Parker added that she was particularly concerned about use and abuse of OTC orlistat by people under age 18.

All panelists were concerned about orlistat interactions with cyclosporine and warfarin. Orlistat's effects on warfarin are presumably related to its effect on vitamin K, which is a fat-soluble vitamin. The proposed label and package includes warnings not to use orlistat if taking warfarin or cyclosporine.

Reduced cyclosporine concentrations have been documented when orlistat and cyclosporine are taken together, and the FDA has received postmarketing reports of reduced cyclosporine concentrations and two cases of acute organ rejection in orlistat users. In several cases reviewed by the FDA, serum cyclosporine levels dropped rapidly when orlistat therapy was started and fell to subtherapeutic levels in several cases. Postmarketing reports of bleeding and increased prothrombin time occurred in people on warfarin and orlistat, presumably as a result of vitamin K malabsorption and insufficiency, according to Dr. Julie Golden, a medical officer in the FDA's division of metabolism and endocrinology products, Rockville, Md.