Propulsid Limited Access Program Allows Off-Label Use To Continue

FDA and Johnson & Johnson are indicating that the new Propulsid limited access program will allow physicians to continue prescribing the drug for more serious conditions than nocturnal heartburn due to gastroesophageal reflux disease, the labeled indication.

The company announced March 23 that it will stop marketing Propulsid (cisapride) in the U.S. July 14, after which the product will be available only through a limited access program.

The program will be designed to help manage risk associated with Propulsid use. Propulsid labeling has been changed five times regarding adverse events since its introduction in 1993. The most recent change was a recommendation in January that patients should have an ECG before beginning Propulsid therapy (¹ (Also see "Propulsid Physician Education On Cardiac Risk To Be Presented To Committee" - Pink Sheet, 31 Jan, 2000.)).

FDA's March 23 "Talk Paper" on Propulsid notes that as of Dec. 31, "use of cisapride has been associated with 341 reports of heart rhythm abnormalities including 80 reports of death."

J&J Pharmaceuticals Group Worldwide Chairman William Weldon told a March 23 teleconference that the program will allow prescribing for "people with a wide variety of serious gastrointestinal problems, such as gastroparesis, pseudo-obstruction, esophagitis, functional dyspepsia and certain life-threatening conditions in pediatrics, in addition to GERD."

"Propulsid is indicated for these disorders in many other parts of the world," Weldon added. "Now through the limited access program, it will be available here for patients with these disorders, people who have no other treatment alternatives and who meet the criteria for the program." Because of the wider range of indications abroad, J&J does not expect international regulatory agencies to limit Propulsid access.

FDA's "Talk Paper" notes that "physicians who are treating patients with severely debilitating conditions for whom they believe the benefits of cisapride may still outweigh its risks are encouraged to contact [J&J subsidiary] Janssen." FDA said there are very few patients who would benefit from Propulsid for the approved indication under the new program.

While there is no data demonstrating that Propulsid works for patients who have failed on other therapies, FDA acknowledged that some physicians believe some patients respond only to Propulsid. The agency also said Propulsid has a unique mechanism of action as a prokinetic, which promotes motility in the intestines. Only one other drug, metoclopramide, promotes GI motility, but it has serious neurological side effects, FDA added.

By deciding to limit Propulsid access, J&J avoided having detailed adverse event data publicly aired at a Gastrointestinal Drugs Advisory Committee meeting scheduled for April 12, as well as the possibility of the committee recommending full product withdrawal.

Janssen made the decision to initiate the limited access program, FDA said. The agency also said that it had already prepared documents for the advisory committee review and that the company was aware that the agency intended to ask the committee to consider different options to manage risk, including product withdrawal and limited access. The advisory committee meeting has been canceled.

FDA and J&J are discussing the design of the program protocol, which J&J expects to be approved by the end of March. Program information will be sent to physicians in April. To assure patient access to the drug during the transition, Janssen will continue to distribute it until July 14, with product expected to remain in pharmacies until mid-August.

Janssen has recommended that physicians involved in the program be investigators answering to independent review boards. Among the criteria physicians will need to document are that patients being prescribed Propulsid have tried other therapies, have had an ECG and are not taking contraindicated drugs, Janssen said. Janssen also expects the protocol to accommodate prescribing for off-label conditions, and that there may be different protocols for different conditions.

Janssen said 350,000 patients in the U.S. are taking Propulsid. U.S. sales in 1999 were approximately $500 mil., roughly half of the product's $950 mil. in worldwide sales. The company is preparing for a sharp decline in sales in 2000. After selling approximately $150 mil. of product worldwide ($50 mil. U.S.) in the first quarter, the company said it has made a conservative estimate of $250 mil. in total sales for 2000.

J&J's norcisapride, a single-isomer version of cisapride with a potentially lower risk of drug-drug interactions and cardiac adverse events, is in Phase II.