Novartis Revises Zelnorm Labeling With Diarrhea, Ischemic Colitis Risk Info

Novartis has revised labeling for the irritable bowel syndrome therapy Zelnorm to include the risk of developing severe diarrhea and ischemic colitis, FDA says in a ¹ 'Talk Paper' issued April 28.

The Zelnorm (tegaserod) ² labeling changes include a warning statement on the consequences of severe diarrhea, as well as a new precaution on post-marketing reports of ischemic colitis.

Between August 2002 and March 2004, FDA received 21 reports of patients who had experienced the "serious consequences" of diarrhea, 20 patients with ischemic colitis and three patients with other types of intestinal ischemia, an FDA ³ 'Q&A' on Zelnorm states.

The diarrhea warning is the first in Zelnorm labeling; the drug was approved in July 2002 for constipation-predominant IBS without a warnings section (⁴ (Also see "Novartis Zelnorm Approval: FDA Accepts Overseas History, Active Surveillance" - Pink Sheet, 29 Jul, 2002.), p. 3).

The new warning states: "Serious consequences of diarrhea, including hypovolemia, hypotension and syncope have been reported in the clinical studies and during marketed use of Zelnorm."

"In some cases, these complications have required hospitalization for rehydration. Zelnorm should be discontinued immediately in patients who develop hypotension or syncope. Zelnorm should not be initiated in patients who are currently experiencing or frequently experience diarrhea."

The revised precautions section discusses the potential for an increased risk of developing ischemic colitis.

"Ischemic colitis, and other forms of intestinal ischemia, have been reported in patients receiving Zelnorm during marketed use of the drug. A causal relationship between Zelnorm use and these events has not been established."

"Placebo-controlled clinical trials of 7,000 patients for three-month duration showed no cases of these events, and would suggest the rate of these events is low."

Zelnorm should be immediately discontinued in patients who develop rectal bleeding, bloody diarrhea or new or worsening abdominal pain, labeling says. Patients presenting with such symptoms should be tested for ischemic colitis, and treatment should not be resumed in those diagnosed with the disease.

GlaxoSmithKline's diarrhea-predominant IBS therapy Lotronex (alosetron) was withdrawn from the market in 2000 following 49 reports of ischemic colitis and 21 reports of severe constipation, including three fatalities (⁵ (Also see "Glaxo Lotronex Withdrawal Follows Failed Risk Management Negotiations" - Pink Sheet, 4 Dec, 2000.), p. 3).

Lotronex has since been brought back on the market under a restricted marketing and distribution program (⁶ , p. 28).

FDA's "Q&A" addresses additional regulatory steps that might be possible in light of the Lotronex safety concerns.

"FDA is not thinking of taking Zelnorm off the market at this time," the Q&A says. "We are adding new information about potential risks of treatment with Zelnorm to the labeling so that doctors and patients can make informed individual treatment decisions."

Furthermore, "FDA has not requested any restrictions on the marketing or distribution of Zelnorm," the agency said. "We will continue to carefully evaluate post-marketing reports in patients receiving Zelnorm and consider any additional changes to labeling or other risk management steps that may be necessary."

FDA's Drug Safety & Risk Management Advisory Committee will receive an update on GSK's risk management program for Lotronex May 5. [Editor's Note: To ⁷ watch a webcast or order a video/DVD of the Lotronex meeting, visit FDAAdvisoryCommittee.com.]

The "post-marketing experience" section of Zelnorm labeling now lists the reported post-marketing adverse events, including ischemic colitis, mesenteric ischemia and gangrenous bowel. "Because these cases are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. No causal relationship between these events and Zelnorm use has been established."

As part of the Zelnorm labeling revision, Novartis has agreed to submit 15-day postmarketing safety reports for "any serious adverse event" related to gastrointestinal, reproductive/urinary or thromboembolic disorders, the ⁸ approval letter says.