Irritable Bowel Syndrome (IBS) Drug Alosetron (LOTRONEX) Withdrawn From the Market

Glaxo Wellcome, the producer of the dangerous irritable bowel syndrome (IBS) drug alosetron (LOTRONEX), announced on November 28, 2000 that, at the request of the Food and Drug Administration (FDA), the drug would be withdrawn from the market. Alosetron caused numerous cases of ischemic colitis, a decrease of blood flow to the GI tract that can lead to inflammation, bleeding, and perforation of the GI tract resulting in infection of the abdominal cavity. Severe constipation was an adverse reaction also seen with alosetron.

Ischemic colitis and severe constipation are not “nuisance” effects that will necessarily go away if the offending drug is stopped. Correction of these adverse reactions may require abdominal surgery and the risks that accompany it, and can result in death.

Alosetron was approved in February 2000 after inappropriately receiving a priority (“fast track”) review by the FDA. The drug was reviewed by the FDA Gastrointestinal Drugs Advisory Committee on November 16, 1999. During this meeting four cases of ischemic colitis that occurred during clinical trials were discussed. Glaxo Wellcome claimed that the cases were not due to the drug, and a majority of the advisory committee voted to recommend its approval for marketing.

The drug was on pharmacy shelves by March 2000 and three months later the FDA called another meeting of the Gastrointestinal Drugs Advisory Committee to discuss safety problems including cases of ischemic colitis and complications of severe constipation. Between February and June, the FDA had received seven postmarketing reports of serious complications of constipation, resulting in hospitalization for six patients, of whom three required surgery. In this same period, the FDA received eight postmarketing reports of ischemic colitis, four of which resulted in hospitalization and the other four in endoscopic procedures.

The FDA’s response to these mounting reports of toxicity was predictable: The agency strengthened warnings on the drug’s labeling, a strategy that has frequently failed to protect patients from adverse reactions. The agency also, for the first time, required pharmacists to distribute FDA-approved risk information with each new and refill prescription for alosetron. This information should be required for all drugs, but in the case of alosetron it appears that written patient information was used as an excuse to keep the drug from being banned.

In the August 2000 issue of Worst Pills, Best Pills News, we listed alosetron as a Do Not Use drug because of the safety problems that were presented at the June 26 committee meeting. On August 31, Public Citizen’s Health Research Group petitioned the FDA to remove it from the market immediately. By this time the FDA was aware of 27 cases of ischemic colitis including those that had occurred during clinical trials. We followed this petition with a letter to FDA Commissioner Jane Henney on October 31, urging again that the drug be withdrawn after we had determined that by October 20 the toll from alosetron had risen to 54 cases of ischemic colitis, including five fatalities.

The FDA continued to receive reports of ischemic colitis and complications of constipation associated with alosetron. Some were reports of death or other serious complications of ischemic colitis that required blood transfusion or surgery. The FDA finally asked Glaxo Wellcome to remove alosetron from the market after an analysis turned up 70 cases of serious reactions to the drug. To place this number in perspective it must be remembered that the FDA estimates that for each report of a serious adverse drug reaction it does receive, 10 go unreported, meaning that instead of a few dozen problem cases, we are talking about several hundred.

Alosetron was a drug that never should have been approved. There was no way to manage the risks that, even before it was marketed, were known to be associated with its use. Which individuals might experience ischemic colitis or severe complications of constipation could not be predicted. Even after the FDA required pharmacists to distribute agency-approved information to patients, including tips on recognizing early symptoms of ischemic colitis and severe constipation, adverse reaction reports continued to mount. Users who did not experience serious problems with this drug got off lucky.

Glaxo Wellcome maintained that those who suffered harm from alosetron did so because doctors prescribed it inappropriately or patients used it incorrectly. They claimed that the problems were not the fault of the drug, and contended that patients suffered because they did not take “personal responsibility” for their own care. This is contemptible victim-blaming.

Questions about alosetron’s safety created tension between individual prescribers and patients who believed the drug was a “miracle” on the one hand, and the FDA which has statutory responsibility for the public’s health on the other. The FDA has no way of knowing how many IBS patients were helped by the drug, especially because there was a dramatic improvement even in the patients who got a placebo (dummy drug) in pre-marketing studies. There is no system of counting who gets hurt, let alone who is helped after approval, and claims that hundreds of thousands of IBS sufferers received remarkable benefit from alosetron are baseless rhetoric. The most objective evidence about the benefits of alosetron came from clinical trials conducted before the drug was approved. Between 10 percent and 15 percent more women patients responded to alosetron compared to quasi-treatment in the form of a placebo. Response to treatment, either with alosetron or placebo, was a subjective score of improvement in symptoms for two weeks out of four in 12-week clinical trials. This is a very low standard for approving a new drug.

Undoubtedly, some patients benefited when they were taking alosetron, but was it because of this drug? Some patients also responded favorably in clinical trials to the placebo. A new drug intended to treat a condition that waxes and wanes is difficult to evaluate, especially where there is a high response to treatment with placebo. Was the response due to the drug or to a placebo effect? Most of the “miraculous cures” with alosetron may very well have been due to a placebo effect. None were seen in the controlled clinical trials conducted before the drug was approved.

Concern for the public’s health intensified as the FDA continued to receive reports of severe reactions associated with the use of alosetron. The FDA’s strategy to manage the risks of this drug had failed. They were unmanageable.

The question that the FDA had to answer was: How many lives must be altered, perhaps permanently, or even lost, because of adverse reactions before alosetron would be removed from the market? To appreciate the FDA’s position ask yourself the same question.

Alosetron’s rapid removal, only nine months after marketing began, should not be viewed as a success of the FDA’s postmarketing surveillance system but rather as a failure of its drug approval process.

Alosetron is the sixth new drug approved since mid-1996 that has been removed from the market for safety reasons. In addition, two drugs approved by the FDA in this time period have been banned in other countries but remain on the market here. For all but one of these drugs, serious safety problems were known before their approval.

New drugs are potentially the most dangerous on the market because of how little is known about their safety at the time they are cleared for marketing. On average only about 3,000 patients receive a new drug under carefully controlled conditions for a limited length of time before it is approved. After approval, however, the drug may be prescribed for a lifetime of use by millions of patients with other diseases taking many other drugs. Drugs that are withdrawn from the market or require extensive new safety warnings usually do so within the first five years after approval. That is the reason for our “five-year rule,” which is explained immediately below.

What You Can Do

You should not use a new drug until it has been on the market for at least five years unless it is one of those rare “breakthrough” drugs that offers a documented benefit over older treatments about whose safety much more is known.