Public Citizen Asks FDA to Immediately Remove Orlistat (XENICAL) from the Market

Public Citizen petitioned the Food and Drug Administration (FDA) on Apr. 10, 2006 to immediately remove the diet drug orlistat (XENICAL) from the market. The basis for the petition is the fact that orlistat can cause pre-cancerous changes in the lining of the intestines called aberrant crypt foci (ACF). The full text of the petition can be found on the Health Research Group Web site. 

Two research pathologists from the Case Western Reserve School of Medicine in Cleveland, OH joined Public Citizen in the petition. Their research, consisting of some 42 scientific papers on colorectal cancer, including 15 specifically on ACF, has helped to establish the relationship between ACF and colon cancer.

Orlistat was approved by the FDA in April 1999 for weight loss and weight maintenance when used in conjunction with a reduced-calorie diet. It is marketed by Roche Laboratories, Inc. of Nutley, NJ.  Like other diet drugs, orlistat was approved by the FDA without scientific evidence showing that there is a health benefit for those who use the drug. In other words, there is no evidence that orlistat, or any diet drug, will reduce risk of premature death or illness associated with long-term obesity and inactivity.

Orlistat works in a different way than other diet drugs. It prevents enzymes in the gastrointestinal (GI) tract from breaking down dietary fats into smaller molecules that can be absorbed by the body. Thus, absorption of fat is decreased by about 30 percent, leading to the drug’s most common adverse effects: oily spotting, gas with discharge, fecal urgency, fatty/oily stools, and frequent bowel movements. Because orlistat reduces the absorption of some fat-soluble vitamins, patients must take a supplement that contains these vitamins (A, D, E, and K) and beta-carotene.

Animal studies submitted to the FDA by Roche in the 1990’s showed that orlistat caused ACF in the colons of rats. These results were recently independently confirmed by research published in the December 22, 2005 issue of the journal Cancer Letters. There is now a large body of scientific literature that acknowledges the importance of ACF as the earliest identifiable neoplastic lesion (abnormal growth) that can be a precursor to  developing cancer in the colon.

The FDA pharmacologist who reviewed the animal data submitted by Roche wrote:

Clearly, Roche was worried about orlistat causing the development of cell proliferation and ACF as they studied this in at least seven studies in the pharmacology submission for the New Drug Application (earlier studies were not available for our review).

Orlistat’s approval was initially delayed because in seven randomized controlled clinical trails submitted by Roche to the FDA, there were ten cases of breast cancer in women taking the drug versus only one case in women given a placebo. The relative risk of getting breast cancer while taking orlistat compared to placebo was calculated several times by both the FDA and Roche and found to vary between four- and seven-fold, depending on the analysis. These results caused the FDA Medical Officer to rescind his original approval of the drug.

One FDA reviewer recommended in her consult that orlistat’s professional product labeling should “address issues related to breast cancer risk” with language similar to that used for the hormone conjugated estrogens (PREMARIN). She also recommended a post-marketing registry be established to collect tumor data. Nevertheless, in the end, the FDA accepted Roche’s assurances that breast cancer was not a drug-related adverse event, and nothing about it appears in the drug’s labeling.

Orlistat is minimally effective as a weight loss agent. In two studies published in the journal Diabetes Care in June 2002 and January 2004, there was only a 2.8 percent absolute difference in weight loss between patients taking orlistat and those on placebo after four years. The group receiving orlistat went from an average weight of 242 pounds to 229 pounds, a loss of 13 pounds. The subjects given the placebo went from average of 242 pounds to 235 pounds, or an average weight loss of seven pounds. Both groups were on a reduced-calorie diet and had help from a dietician and encouragement to exercise throughout the study. Study participants regained much of their initial weight loss over their four years on drug.

The FDA recognizes that there is no evidence that orlistat has a health benefit in terms of reducing the illness and death that is associated with obesity and physical inactivity. The FDA-approved professional product label for orlistat states that “The long-term effects of orlistat on morbidity and mortality associated with obesity have not been established.”

The FDA is in the process of deliberating the switch of orlistat from prescription to over-the-counter (OTC) status at a dose starting at one-half that of the prescription product. In light of the association between orlistat and ACF and the lack of a proven health benefit with the use of the drug, such a switch is ill-advised.

What You Can Do

You should not take orlistat. There is no evidence that this drug can reduce the health risks associated with obesity and inactivity, and the drug’s minimal effectiveness for weight loss-coupled with both the real and theoretical risks of orlistat-outweigh any known benefit for the drug. Clearly, this drug should come off the market immediately.