Unsafe IBS Drugs Back on the Market

Taken from the July/August 2007 issue of the Women's Health Activist Newsletter.

IBS patients may have predominantly constipation or diarrhea, or may have alternating bouts of diarrhea and constipation. Some also have abdominal pain, flatulence, nausea, or loss of appetite.

IBS doesn’t progress and isn’t dangerous, but it can be extremely unpleasant for severe sufferers. Its symptoms may be preferable, however, to two pharmaceutical IBS treatments that have been linked with adverse effects so severe that the drugs were withdrawn from the market. Both drugs are still available, though.

Drugs don’t seem to disappear anymore, they just lay low until the scandal dies down and then sneak back to town. The latest boomerang drug is Zelnorm® (tegaserod), which was approved in July 2002 for short-term treatment of women with IBS who have constipation; and for patents younger than 65 with chronic idiopathic constipation (defined as “fewer than three compete spontaneous bowel movements per week and at least one of the following symptoms for at least 25% of those bowel movements: straining, hard stools, incomplete evacuation”). Those criteria, of course, cover lots of elders, dieters, and people who don’t ingest enough fluid or fiber. “Idiopathic” means “without a recognized cause”, so this is garden-variety constipation. The drug isn’t approved for the very severe constipation caused by neurological diseases, injuries, or medications.

Zelnorm was withdrawn from the market in March 2007, after being linked to high rates of heart attacks, strokes, and unstable angina. In July, 2007, Zelnorm was back — resurrected under a “treatment IND.” IND stands for “Investigational New Drug” and usually refers to a drug that’s being tested in clinical trials before an application for drug approval. A treatment IND (also called a “compassionate IND”) is sometimes invoked to make an experimental drug available to those with life-threatening illnesses before testing is finished. For example, AZT, the first drug to treat AIDS, was made available under a compassionate IND. (Its availability limited the number of people who entered a clinical trial and delayed, by years, the discovery that it was no miracle cure. In retrospect, AIDS patients would have been better served by scientific evaluation of the drug.)

At any rate, constipation is not AIDS, and the concept that constipated patients should have access to a dangerous drug under a compassionate IND would be funny if it weren’t appalling. In 29 placebo-controlled trials, including 11,614 patients treated with Zelnorm and 7031 treated with placebo, 13 treated patients (0.1%) and one placebo-treated patient (0.01%) had life-threatening cardiovascular adverse effects. Besides cardiovascular problems, Zelnorm’s been linked to severe diarrhea and ischemic colitis, a life-threatening condition where part of the colon dies from lack of blood flow. Under Zelnorm’s “treatment IND”, the manufacturer will supply the drug without cost to women who are under 55 years with IBS with either constipation or chronic idiopathic constipation; who either took it successfully before or haven’t had a response to other available treatments; and have no history, symptoms, or risk factors for cardiovascular disease, and aren’t depressed, anxious, or suicidal (www.zelnorm.com). If you’re not eligible, other options for getting the drug may be available.

Limiting the treatment population to healthy women under 55, of course, makes it extremely unlikely that any heart attacks will occur. The manufacturer will most likely resubmit the drug to the FDA and get approval for women under 55 with no cardiovascular risk factors. Once it’s back on the market, Zelnorm will be prescribed more broadly.

This feels like déjà vu all over again. Another IBS drug, Lotronex® (alosetron), was approved for diarrhea-predominant IBS in February 2000; it was withdrawn before the end of that year because it was linked to ischemic colitis. In 2002 — despite more than 100 hos-pitalizations, 50 surgeries, and seven deaths linked to the drug — Lotronex was back on the market under a “risk-management program”. The advisory committee that evaluated the drug in 2002 recommended that the drug should only be prescribed by physicians who’ve been trained and certified; yet, the FDA ignored its own committee and stated, essentially, that physicians could assess their own qualifications. Physicians who prescribe Lotronex under the risk management program must sign a form saying that they have read the full prescribing information, know what the drug is used for, and have explained the risks of the drug to the patient. (Hmm, shouldn’t physicians do that for all drugs?) Patients must sign a consent form (as they do for Zelnorm as well).

“Risk management” programs” and “treatment INDs” may become the new norm for keeping, or returning, dangerous drugs to market. Drugs are supposed to be safe and effective for the conditions for which they are approved. Heart attacks and rotting colons are not a reasonable trade-off for constipation and diarrhea treatments. The Lotronex case was called “a case study in regulatory capture”, meaning that pharmaceutical companies were controlling the FDA’s actions. Allowing a treatment IND for Zelnorm strengthens that criticism.

Adriane Fugh-Berman, MD, is a former NWHN Board Chair whose research presents a critical analysis of the marketing of prescription drugs. Adriane educates prescribers on pharmaceutical marketing practices as Director of the PharmedOUT program, and created the Health in the Public Interest program at Georgetown University School of Medicine where she trains a new generation of consumer advocates.

Read more from Adriane Fugh-Berman.

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Food and Drug Administration (FDA), “FDA Public Health Advisory: Tegaserod maleate (marketed as Zelnorm).” Rockville, MD: FDA. March 30, 2007. Online at: fda.gov/cder/drug/advisory/tegaserod.htm.

Moynihan R. “Alosetron: a case study in regulatory capture, or a victory for patients’ rights?” BMJ 2002; 325:592-595. Online at: http://www.bmj.com/cgi/newsletterarticles/full/325/7364/592.

Moynihan R. “FDA advisers warn of more deaths if drug is relaunched”. BMJ 2002; 325: 561.

Horton R. “Lotronex and the FDA: a fatal erosion of integrity.” Lancet 2000; 357:1544-1545.

Food and Drug Administration (FDA), “FDA News Release: FDA permits restricted use of Zelnorm for qualifying patients.” Rockville, MD: FDA, July 27 2007. Online at: www.fda.gov.

Public Citizen. Problems in the new drug approval process: a case study of Lotronex. Washington, DC: Public Citizen, April 23, 2002. Online at: www.citizen.org/congress/regulations/issue_areas/drug_devise/articles.cfm?ID=7442.