FDA Committee Reviews Orlistat as an Over-the-Counter Agent

On January 23, an FDA Advisory Committee began reviewing a New Drug Application for what could be the first nonprescription weight-loss drug approved for use in the U.S. The new application was for the lipase inhibitor orlistat (Xenical®), and was submitted by GlaxoSmithKline Consumer Healthcare.

Orlistat inhibits pancreatic lipases, thus reducing intestinal absorption of dietary fat. When the capsules are taken three times a day with meals, about 25% of any fat consumed in the meal is blocked from absorption. That fat, which is the equivalent of about 150 to 200 calories, is then excreted in the stool. The drug is designed for patients who are at least 30% above their ideal weight, or who have a body mass index (BMI) of 30 kg/m2 or more.

The recommended dosage is 120 mg at each main meal that contains fat. Because orlistat works by blocking the absorption of dietary fat, it usually produces some changes in bowel habits, including oily spotting of the rectum, flatulence, fecal urgency, and for some, fecal incontinence. And, because the drug interferes with the body’s absorption of some fat-soluble vitamins, patients are advised to take a daily multivitamin supplement that contains vitamins D, E, K, and beta-carotene.

GlaxoSmithKline Consumer Healthcare has said that providing a half-dose version of the drug, or doses of 60 mg, could promote weight loss in overweight adults when combined with a reduced calorie, low-fat diet and a suggested exercise regimen. Cutting the dosage in half would also lessen the unpleasant gastrointestinal effects that have made patients stop taking the drug.

The over-the-counter product will be named Alli. Glaxo estimates that 5 to 6 million adult Americans could buy the pills, which would cost from $12 to $25 per week.

The company has also said that making the drug available without a prescription will make it easier for overweight Americans to seek treatment for obesity. While numerous dietary supplements, including herbal preparations and other products, are available without prescription, there is as yet no FDA-approved nonprescription treatment for obesity. Orlistat’s main rival is Meridia®, produced by Abbott Laboratories; this product acts by suppressing appetite.

Orlistat in 120-mg capsule form will remain a prescription drug for those who should be treated under the care of a physician.

Several of the advisory board members have been concerned that some consumers may not be able to tell whether Alli is safe for them, and questioned its efficacy, noting that most people who take the drug regain weight once they stop using the drug.

Precautions for those with eating disorders

Orlistat is currently not recommended for use by patients with anorexia nervosa or bulimia nervosa. Glaxo representatives have reported that there is a very low potential for abuse or misuse of the nonprescription form of the drug, since there have been only 4 published reports of bulimics misusing the drug, while more than 22 million people worldwide have taken it.

In contrast, some researchers have pointed out that at least some eating disorders patients in the community are likely to abuse Alli just as they abuse laxatives, regardless of how the product label and patient information inserts may warn of this. Other patients also will not take supplemental vitamins and may develop deficiencies of fat-soluble vitamins—again, regardless of the warnings on the label.

Abuse among patients with bulimia nervosa

Three cases have demonstrated how patients can abuse orlistat. Physicians at University Hospital of Bellvitge, Barcelona, Spain, reported two cases of misuse of orlistat in two normal–weight women who used orlistat as a purging mechanism after binge-eating episodes (Int J Eat Disord 2002;30:458).

In both cases, the women had begun binge eating and purging in adolescence. From the beginning, both women had used a restrictive diet, binge eating, and purging (vomiting and using laxatives). Both women misused orlistat as their only purging mechanism after every binge episode. The authors concluded that although bulimia nervosa patients have used many substances and bizarre behaviors as purging mechanisms after binge eating, these were the first reported cases of use of orlistat as the sole purging mechanism.

In another study, Drs. Shisuka Malhotra and Susan L. McElroy reported a case of a patient who used orlistat as a weight-loss behavior to compensate for binge eating (Am J Psychiatry 2002;159:492). The patient was a 49-year-old woman who enrolled in a weight management program for extreme obesity. She weighed 287 lb and had a body mass index of 45 kg/m2. At the first assessment she met DSM-IV criteria for bulimia nervosa, purging type, and also major depressive disorder, which was diagnosed through a structured interview.

The patient’s binge eating began at 9 years of age; she weighed 140 lb by age 10. Her binge eating and weight gain continued throughout high school and college. By the time she was 25, she was binge eating once or twice a day and weighed 206 lb. She took laxatives to relieve her ‘feeling of fullness’ once or twice a month but at this time did not use regular compensatory weight-loss behaviors.

The patient had tried nine weight loss programs and two over-the-counter appetite suppressants over several years. One year before enrolling in the authors’ obesity treatment program, she had begun using orlistat, 120 mg three times a day, as prescribed by her internist. Although she continued to binge eat 4 or 5 times a week, she lost 45 lb after 6 months. Because of financial problems, she stopped taking the drug and regained all the lost weight within 4 months.

She began ordering orlistat over the Internet, and used the drug only during binge-eating episodes in order to save money. When she came to the program, she had lost 5 lb in 2 months. However, now she was binge eating 4 to 7 times a week, using orlistat during every binge. She had 4 to 7 bowel movements a day, moderate-to-severe fecal urgency, oily rectal spotting, and flatulence after every binge episode. She began avoiding most social situations because of the drug’s side effects. The authors suggested that the drug might be reinforcing her binge eating and suggested that it be discontinued; the patient was reluctant to stop taking it, believing that it helped prevent weight gain.

According to the authors, although the medication did help regulate the patient’s obesity, it did not help her binge eating or depression. They note that this case raises the importance of assessing psychiatric conditions (especially mood and eating disorders) among persons seeking treatment of weight loss.

Is orlistat an option for treating binge-eating disorder?

As many as half of people who participate in weight-loss programs have signs of binge eating disorder (BED). Until recently, people with BED have been excluded from orlistat treatment programs in the past.

A group at University Hospital, Geneva, Switzerland, headed by Dr. Alain Golay and assessed the efficacy of orlistat in 89 obese patients with BED (Obes Res 2005;13:1701). All patients had clinically diagnosed BED and body mass indexes greater than 30 kg/m2. (One of the investigators was employed by Roche Pharmaceuticals, the original parent company.) In a double-blind study, the patients were randomized to 24 weeks of treatment with 120 mg orlistat or placebo, three times a day. They were also placed on a mildly reduced-calorie diet.

Greater weight loss was reported in the orlistat group

After 24 weeks, the mean weight loss for those in the orlistat treatment group was significantly greater than for patients receiving placebo: -7.4% vs. –2.3%, respectively. Also, the overall Eating Disorder Inventory-2 score at 24 weeks was significantly lower in patients treated with orlistat than those in the placebo group. The authors concluded that orlistat can be considered part of the management program for obese patients with BED.

Panel requests follow-up studies

If Alli is approved and does reach the market as an over-the-counter product, the FDA panel has requested that Glaxo conduct follow-up studies. They also requested that the company redesign the product label to ensure that it will be used properly and to include proper warnings for consumers.