A risk management program to track postmarketing incidences of ischemic colitis with Glaxo Wellcome's Lotronex will be discussed at the June 27 meeting of FDA's Gastrointestinal Drugs Advisory Committee.

The irritable bowel syndrome therapy Lotronex (alosetron) has produced a few reports of acute ischemic colitis since its U.S. launch in March, the company said.

The postmarketing reports are consistent with labeling, Glaxo said. Lotronex labeling warns that "acute ischemic colitis was infrequently reported" in three-month trials. "Infrequently" is defined as .1% to 1% incidence.

Labeling adds that "a causal association between treatment and acute colitis has not been established, nor have risk factors been identified." Glaxo agreed to conduct a Phase IV trial to assess the risk of colitis (¹ Also see "Glaxo Lotronex Studies May Expand Market To Men, Teens, Pediatrics" - Pink Sheet, 14 February, 2000.).

The original user-fee goal date for Lotronex, at the end of 1999, was extended three months because of a submission by Glaxo of additional safety information. During its November review, the advisory committee requested more information on ischemic colitis, constipation, and use in patients with elevated liver enzymes (² Also see "Glaxo Lotronex Indication Would Cover One-Third Of IBS Patients" - Pink Sheet, 22 November, 1999.).

Glaxo is still looking into cases of acute ischemic colitis that have occurred since the drug was launched, and expects to have reports on each individual case to present to the advisory committee.

The discussion by the advisory committee does not appear to be the result of an unexpected defect in the drug, but rather of a shift in FDA policy towards developing risk management plans for certain products.

During a Food & Drug Law Institute meeting in Washington, D.C. June 5, Center for Drug Evaluation & Research Director Janet Woodcock, MD, said that postmarketing risk management programs should become routine (³ Also see "Rx Risk Management Programs May Become Routine Element In FDA Reviews" - Pink Sheet, 12 June, 2000.).

The Lotronex committee discussion will focus on developing a program which will include a component to educate physicians and patients as to who is an appropriate candidate for therapy, Glaxo said.

Postmarketing adverse events of constipation will also be discussed by the advisory committee in consideration of the risk management plan, the company added. Glaxo said the reported incidence of mild-to-moderate constipation does not match product labeling, which cites a 25%-30% rate in women with diarrhea-predominant IBS.

The advisory committee recommended approval of the drug only for women with diarrhea-predominant IBS. However, the indication for Lotronex allows use in women whose symptoms alternate between diarrhea and constipation.

One focus of discussion is likely to be whether the level of reporting of colitis suggests an incidence that may be higher than labeling suggests. FDA typically estimates that the actual prevalence of a side effect can be as much as 10-fold higher than the reported incidence.

If the reported rate of constipation is significantly lower than the labeled incidence, that could support an argument that the incidence of colitis is higher than the reporting rate suggests. However, Glaxo points out, postmarketing reports for a mild condition like constipation are likely to be less common than for a more serious condition like acute colitis.

Although FDA intends to make risk management programs a more routine part of product regulation, Glaxo Wellcome is unlikely to relish the opportunity to be one of the first companies to have to explain FDA's policy to physicians, consumers and shareholders.

Lotronex is being watched closely by the financial community as the major product launch for Glaxo - and the merged Glaxo SmithKline - in 2000.

Another potential IBS product, Novartis' Zelmac, is undergoing priority review at FDA, with an advisory committee review scheduled for June 26. The juxtaposition of a positive review for Zelmac with a discussion of adverse event reports for Lotronex would be awkward for Glaxo.

Another early attempt by FDA to use a risk management program generated attention June 6, when Planned Parenthood raised objections to the proposed restrictions on distribution for the abortifacient mifepristone (⁴ Also see "RU-486 Action Date Is Sept. 30; Allen Named Reproductive Division Director" - Pink Sheet, 12 June, 2000.).

Lotronex Advisory Committee Will Discuss Program For Ischemic Colitis Risk

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