FDA Panel Backs Prucalopride for Chronic Idiopathic Constipation

Troy Brown, RN

October 18, 2018

The Gastrointestinal Drugs Advisory Committee of the US Food and Drug Administration (FDA) voted unanimously (10 yes, 0 no) to recommend prucalopride tablets (Shire Development) for the treatment of adults with chronic idiopathic constipation (CIC).

The panel also voted unanimously (10 yes, 0 no) that the applicant adequately addressed the potential risk for cardiovascular adverse events with the use of prucalopride in adults with CIC and that the risk–benefit profile of prucalopride supports the approval of the application.

CIC affects approximately 35 million individuals in America and prucalopride is currently the only 5-hydroxytryptamine4 (5-HT4) agonist available in the United States for treatment of the disorder. Prucalopride is a gastrointestinal prokinetic agent that improves bowel motility by stimulating colonic peristalsis. Although currently an investigational compound in the United States, it has been approved in the European Union and other countries outside of Europe for chronic constipation.

The FDA inactivated the investigational new drug (IND) application for prucalopride as a result of genotoxicity and carcinogenicity concerns on July 30, 2004, as reported by Medscape Medical News. The FDA reactivated the IND in September 2012.

"My concerns were more for long-term carcinogenicity potential with the drug but then [with] the current information benefits outweigh risks," committee chairperson Jean-Pierre Raufman, MD, professor and head, Division of Gastroenterology & Hepatology, University of Maryland School of Medicine, Baltimore VA Maryland Health Care System, said at the meeting.


The panel's vote follows consideration of data from five randomized, double-blind, placebo-controlled phase 3 trials and one phase 4 double-blind, placebo-controlled trial in patients with CIC from four continents. Four studies — studies 3001, INT-6, USA-11, and USA-13 — evaluated prucalopride 2 mg/day compared with placebo. Studies 302 and 401 evaluated prucalopride 2 mg/day in patients younger than 65 years; patients aged 65 years and older began with prucalopride 1 mg/day and had the option to dose-escalate to 2 mg/day if they experienced insufficient response to therapy. The researchers defined insufficient response as an average of less than three spontaneous complete bowel movements (SCBMs) per week during the preceding 2 weeks of treatment at the week 2 or week 4 visit.

An integrated efficacy analysis from the trials that included 2484 patients found that significantly more of them had an average of at least three SCBMs per week during 12 weeks of treatment compared with placebo (27.8% vs 13.2%; odds ratio, 2.68; 95% CI, 2.16 - 3.33; P < .001).

Clinically meaningful improvement in bowel function with an average increase of at least one SCBM per week over 12 weeks was experienced by 47.0% of patients in the prucalopride group compared with 29.9% of patients in the placebo group (P < .001). Patients on prucalopride experienced significant reductions in time to first SCBM and significant reductions in the use of rescue medication for the mean number of tablets and mean days of use (P < .001).


In the integrated safety analysis of 2552 patients, 806 patients (63.3%) taking prucalopride and 682 patients (53.3%) taking placebo experienced at least one treatment-emergent adverse event (TEAE).

Most of the TEAEs experienced by patients in the prucalopride and placebo groups were mild or moderate in severity. The most commonly seen TEAEs that occurred in 5% or more of the treatment group were gastrointestinal disorders including nausea, diarrhea, abdominal pain, and headache. Adverse cardiovascular events occurred in comparable percentages among the treatment and placebo groups (2% vs 1.8%). Serious TEAEs were experienced by 1.6% of the treatment group compared with 2.4% of the placebo group; no patients died from TEAEs.

Similar drugs have been previously linked to adverse cardiovascular events; therefore, the company included findings from a real-world observational safety study in the new drug application to estimate the risk for these types of events in patients taking prucalopride compared with polyethylene glycol. SPD555-802 was a post-marketing retrospective cohort (observational) study that assessed the incidence of major adverse cardiovascular events (MACE) in European patients exposed to prucalopride or polyethylene glycol 3350. The study found "no evidence of an increased risk for MACE in patients with chronic constipation using prucalopride as compared with PEG," according to the FDA's briefing document.

Fewer men than women reported at least one TEAE in the prucalopride group (47.2% vs 68.5%, respectively) and placebo group (38.5% vs 58.0%, respectively).

There were two suicides among patients taking prucalopride, neither of which was deemed related to the study drug.

"I remain concerned about the psychiatric complaints and believe that the study could be done just to look at completed suicides. I would like it to be done; however, I do believe that there's a great unmet need and believe the potential benefits of this drug outweigh those concerns," voting committee member Jennifer C. Lai, MD, MBA, associate professor of medicine and director of Gastroenterology/Hepatology, University of California, San Francisco (UCSF), said at the meeting.

Of those in the treatment group, 5.2% of patients permanently discontinued the treatment drug compared with 3.4% of patients in the placebo group.

"I do think that it is important to have more long-term evidence for chronic therapies, both from an efficacy and safety standpoint," temporary voting member John Teerlink, MD, professor of medicine, UCSF; director, Heart Failure; and director, Echocardiography, Section of Cardiology, San Francisco Veterans Affairs Medical Center, California, said at the meeting.

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