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Executive Summary

JANSSEN's PROPULSID GASTRIC MOTILITY AGENT IS "APPROVABLE" as of April 9 for symptomatic treatment of patients with nocturnal heartburn due to gastroesophageal reflux disease (GERD). The NDA (20-210) for Propulsid (cisapride) was filed Aug. 29, 1991. FDA's Gastrointestinal Drugs Advisory Committee unanimously recommended approval of Propulsid for the treatment of symptoms of GERD in April 1992 ("The Pink Sheet" April 20, 1992, p. 3). The committee's recommendation was based mostly on Propulsid's efficacy in treatment of nighttime heartburn. Janssen presented the committee with results from three U.S. multicenter, double-blind trials of cisapride compared to placebo in 506 GERD patients. The trials' efficacy endpoints included heartburn (nighttime, daytime and combined), antacid use, regurgitation, physician global assessment and patient global assessment. Two of the trials were 12-week studies comparing cisapride 10 mg, cisapride 20 mg and placebo. In one of the trials (1201), the group that received 10 mg cisapride q.i.d. achieved statistical significance in terms of the investigator's scoring of nighttime heartburn (using a scale of moderate to severe) and a similar effect was recorded in patients' diaries, an FDA medical reviewer told the committee. In trial 1203, both cisapride regimens showed improvement in night-time heartburn as assessed by patients. A "significant improvement" was seen with the 20 mg q.i.d. dose and "statistical significance" was achieved with the 10 mg q.i.d. dose at the fourth week, the reviewer said. A majority of the committee members concluded that 10 mg of cisapride q.i.d. should be the recommended starting dose for treating GERD patients. Janssen conducted drug interaction studies that showed cisapride concentrations increased 30-40% in the presence of SmithKline Beecham's Tagamet (cimetidine), but showed no increase in cisapride absorption when coadministered with Glaxo's Zantac (ranitidine). Studies also showed that cisapride accelerated the absorption and increased the concentration of Tagamet and Zantac. At the time, Janssen had not studied cisapride in combination with Merck's proton-pump inhibitor Prilosec (omeprazole). Based on committee recommendations, Propulsid labeling most likely will carry information about the incidence of seizure, seizure-like events and liver-enzyme changes. The company told the committee that the worldwide database included 20 reports of seizures in patients in clinical trials and three from postmarketing reports. Janssen also listed 19 seizure- like events in the NDA. Liver abnormalities were seen in 18 patients, 10 in the U.S. Janssen said that a statement about the seizures was in proposed labeling, but pointed out that none of the seizures occurred in patients with GERD.

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