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Groups argue over FDA'S IBS drug decision

From the Science & Technology Desk
Published 6/11/2002 2:10 PM
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ROCKVILLE, Md., June 11 (UPI) -- Consumer groups are both criticizing and praising the Food and Drug Administration for allowing the reintroduction of Lotronex, a controversial drug used to treat irritable bowel syndrome.

FDA announced on Friday it was authorizing return of Lotronex, despite several deaths and numerous reports of complications previously associated with its use. The renewed approval contains restrictions for women with severe, chronic cases of diarrhea-predominant IBS. The drug, also known as alosetron hydrochloride, was approved in February 2000 and withdrawn by its manufacturer GlaxoSmithKline in November 2000.

Public Citizen, the non-profit public interest group, strongly criticized the agency's decision, arguing the restrictions should be far stricter and warning patients will be endangered by the drug. In contrast, the Lotronex Action Group, representing patients of the IBS Self Help Group who have benefited from the drug and have been advocating continuing access, applaud FDA's action, but wish for less onerous restrictions.

The conflict comes at a unique moment in FDA drug approval history. The Lotronex decision represents the first time the agency has agreed to allow back on the market a drug that had been voluntarily withdrawn.

"It represents the FDA trying to balance access to effective therapy for disabling conditions against trying to protect the public from harm due to adverse effects," Dr. Victor Raczkowski, acting director, of the FDA's Division of Gastrointestinal and Coagulation Drug Products, told United Press International. "We feel this new risk management program strikes a reasonable balance."

Raczkowski added, "One of the unique features was that there weren't other effective therapies for these patients to turn to."

He said one of the features of the new program was to start patients at half the originally approved dose. The new dosing guidelines would start patients at one milligram a day, instead of two a day.

"It's a prudent move to start at a lower dose," to better manage and monitor risks, particularly the risk of constipation, which increases as the dose increases.

Lotronex was withdrawn after reports of ischemic colitis, resulting in 54 patients requiring hospitalization, two patients receiving blood transfusions, 11 surgeries and two days. Serious complications of constipation resulted in 83 patients requiring hospitalization, 34 undergoing surgery, two receiving blood transfusions and two deaths.

"We are quite fearful for patients," Larry Sasich, a pharmacist and research analyst with Public Citizen's Health Research Group, said in a statement. "Unfortunately, the FDA's action will almost surely lead to more injuries and possibly deaths associated with this drug."

In its statement on the drug's reintroduction, Public Citizen said not only is the new marketing program too lax to prevent harm, but it is to be overseen by the company that makes the drug -- a poor idea because the company has a financial incentive to downplay problems with the drug. Also, the new recommended starting dose of one milligram has not been shown to be effective, they said.

But Jeffrey Roberts, president and founder of the IBS Self Help Group, who has been suffering with diarrhea-predominant IBS for 25 years, sees the matter very differently.

Roberts told UPI he took one milligram a day of Lotronex and found it very effective. He had both pain and diarrhea for a quarter century -- until then.

"The symptoms went away in three days. Something I hadn't achieved ever. It was a little odd I have to admit. It took a little while to get used to the new freedom."

Combinations of other drugs never worked as well, Roberts said, adding many in his group have been using another GlaxoSmithKline drug -- Zofran -- which closely resembles Lotronex chemically. Zofran is approved for prevention of nausea and vomiting induced by chemotherapy, radiation and postoperative effects. However, it is much more expensive and there are no long-term studies of IBS patients using the drug, Roberts said.

Roberts told UPI he has trouble understanding why Public Citizen chose to oppose a drug that has had such a remarkable impact on his life and on many others in his group.

"Obviously, it was very difficult for us. This was a group that was supposed to be representing consumers, and we had to represent ourselves. The quality of life is so poor when you have IBS, (Public Citizen) failed to understand the benefits far outweighed any risks," Roberts said.

Roberts also noted many people in his group have found even half a milligram a day or every other day has been effective, a smaller dose than the amount Public Citizen claims is ineffective. He knows no one who took two milligrams daily -- as recommended under the original approval guidelines in 2000 -- on a long-term basis.

Ramona DuBose, spokeswoman for GlaxoSmithKline in Research Triangle Park, N.C., told UPI, "We believe this risk management plan is very a effective tool to guide physicians and patients in the proper use of Lotronex. We will certainly monitor the plan and will be meeting with FDA regularly and if we see weaknesses we will certainly modify the program."

When asked about starting patients on the lower dose according to the new guidelines, and the Public Citizen claim that the dose was ineffective, she said, "In the original trial there was an effect seen at one milligram a day. But the most efficacious was one mg two times a day."

Told about Roberts' own experience and those of many in his group who have seen benefits at even lower doses and intermittent doses, DuBose replied, "It's so important for physicians to work with patients on what works with them."

FDA's Raczkowski said the company estimates the market for the drug under the new restrictions is about 185,000 women. DuBose said the drug would be available in several months, but acknowledged she did not know how much the drug would cost in the new program.

Among the restrictions, "The drug's indication has been narrowed to be only for treatment of women with severe, diarrhea-predominant Irritable Bowel Syndrome (IBS) who have failed to respond to conventional IBS therapy. Limiting the use of Lotronex to this severely affected population is intended to maximize the benefit to risk ratio," FDA said in a statement.

Ironic, but some of Lotronex's most vocal advocates have been men, including Roberts, Raczkowski said, even though, so far, in rigorous studies, it has not been shown to be safe and effective in men. That does not mean Lotronex does not work in men, he said. It is just the studies have not been done in men.

Meanwhile, Raczkowski said, FDA is requiring GlaxoSmithKline to complete and submit by fourth quarter 2005 a phase 4 post-marketing study on the drug. The study will be designed to determine, among other things, whether lower doses and intermittent doses are effective.

In the United States, 30- to 40-million people suffer from IBS, which includes several symptoms, including bloating, abdominal pain, either constipation or diarrhea or an alternating from one to the other. Researchers said it is a functional disorder of the gut, and there is no one cause that triggers it in all sufferers.

Less than 5 percent of IBS is considered severe, and only a fraction of severe cases are diarrhea-predominant. Severe IBS is a chronic condition (in this case, generally lasting more than six months) with symptoms that disable or significantly curtail the daily activities of patients. Symptoms typically include frequent and severe abdominal pain and fecal incontinence, or an uncontrollable urge to have a bowel movement.

The more common form of IBS is constipation-predominant. Another drug, Tegaserod, manufactured by the Swiss company, Novartis Pharmaceuticals Corp., is under review by FDA for that indication.

(Reported by Larry Schuster, UPI Science News, in San Francisco)

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