U.K. Use Of J&J's Cisapride Halted Pending 2001 Ruling On Status In EU

The U.K.' s Medicines Control Agency is withdrawing Johnson & Johnson's cisapride from the market, pending a decision on the drug's status in the EU, expected in 2001.

As of July 28, "all treatment with cisapride should be stopped and patients should be changed to alternative treatment as necessary," a July 19 Dear Doctor letter from MCA's Committee on Safety of Medicines states.

Regulatory authorities in Germany, Canada and the U.S. have also halted or restricted cisapride sales due to the risk of QT prolongation and drug-drug interactions. J&J announced March 23 that it would stop marketing Propulsid in the U.S. July 14, after which the product will be available only through a limited access program (¹ (Also see "Propulsid Limited Access Program Allows Off-Label Use To Continue" - Pink Sheet, 27 Mar, 2000.)).

J&J reported second quarter Propulsid/Prepulsid sales at $104 mil., down 64% from the second quarter of 1999. Sales in the first quarter totaled $160 mil.

The EU's Committee for Proprietary Medicinal Products is reviewing the use of Prepulsid (marketed as Propulsid in the U.S.) and intends to issue a decision during the first half of 2001 on "what indications for cisapride, if any, are justified," the U.K. Department of Health said. The decision will be binding on all EU member states.

J&J plans to submit a reanalysis of risk/benefit data for cisapride to the CPMP in September.

The U.K. will suspend Prepulsid's marketing license until the CPMP review is completed because "previous action by the CSM has only had a limited effect in reducing co-prescribing of cisapride with contraindicated medications," the dear doctor letter states. "Serious cardiovascular reactions, including fatalities, continue to be reported."

A study conducted by the FDA Division of Drug Risk Evaluation II similarly concluded that no reduction in contraindicated use of cisapride was found following labeling changes and a Dear Doctor letter in June 1998.

Division Director Evelyn Rodriguez, MD, presented the study at the July 19 advisory committee review of Pfizer's Zeldox, which also has a QT prolongation effect, although it does not appear to be exacerbated by concomitant drugs (² (Also see "Zeldox QTc Prolongation Is Less Severe Than Serlect, Pfizer Tells Committee" - Pink Sheet, 24 Jul, 2000.)).

FDA found that of cisapride prescriptions written through Tennessee Medicaid (1.4 mil. lives) in the year following the dear doctor letter, 57% were for patients for whom the drug was contraindicated. Before the label change, 60% of prescriptions were for uses that would later be contraindicated, Rodriguez reported.

In the United Health Group (3.2 mil. lives), 27% of cisapride Rxs were for contraindicated patients after the letter was sent, compared with 29% before. The Harvard Consortium HMO (2 mil. lives) included 28% inappropriate cisapride prescriptions after June 1998, compared with 30% before.

Educational efforts in the U.K. have included a 1998 CSM bulletin for physicians and pharmacies listing all drugs contraindicated with cisapride, and three warning letters to doctors on safety information and changes to labeling issued by the company since 1995.

Since 1988, there have been 60 reports of serious cardiovascular adverse events in the U.K., five of which were fatal. Worldwide, there have been 386 reports of serious ventricular arrhythmias (125 fatal) attributed to cisapride, and 50 reports of sudden unexplained death, CSM said.

In the U.K., doctors can prescribe suspended products under the "named patient use" scheme. A company may apply to the MCA for permission to import a drug based on physician requests. MCA can deny this application but has indicated that J&J can supply the drug under certain conditions, such as with the reassurance that it is used as second or third line therapy after patients have failed other medications, the company said.

The company has not promoted Prepulsid in the U.K. for the past several years, J&J said, but the product remains among its top six selling drugs in that market.

The U.K. Department of Health listed "antacids, H2 antagonists (e.g. cimetidine and ranitidine), prokinetic agents (e.g. metoclopramide and domperidone) and proton pump inhibitors (e.g. omeprazole)" as therapeutic alternatives for cisapride patients in a statement announcing the withdrawal. All of the agents listed are available in generic form or are expected to be available shortly.