FDA OKs Prucalopride (Motegrity) for Chronic Idiopathic Constipation

Megan Brooks

Disclosures

December 18, 2018

The US Food and Drug Administration (FDA) has approved prucalopride tablets (Motegrity, Shire PLC) for adults with chronic idiopathic constipation (CIC).

CIC affects roughly 35 million adults in the United States. Prucalopride, a selective serotonin–4 (5-HT4) receptor agonist, enhances bowel motility by stimulating colonic peristalsis.

In October, the FDA's Gastrointestinal Drugs Advisory Committee voted unanimously to approve prucalopride for adults with CIC, as reported by Medscape Medical News.

The committee considered data from five randomized, double-blind, placebo-controlled phase 3 trials and one phase 4 double-blind, placebo-controlled trial that included a total of 2484 patients with CIC. Four studies evaluated prucalopride 2 mg/day in comparison with placebo. Two evaluated prucalopride 2 mg/day in patients younger than 65 years. For patients aged 65 years and older, prucalopride was administered at an initial dosage of 1 mg/day; the dosage could be escalated to 2 mg/day if the response to therapy was insufficient.

An integrated efficacy analysis from the trials found that significantly more patients who took prucalopride experienced an average of at least three complete spontaneous bowel movements per week during 12 weeks of treatment compared with patients who were given placebo (27.8% vs 13.2%; odds ratio, 2.68; 95% confidence interval, 2.16 - 3.33; P < .001).

Forty-seven percent of patients taking prucalopride experienced clinically meaningful improvement in bowel function, with an average increase of at least one complete spontaneous bowel movement per week over 12 weeks, compared with 29.9% of patients taking placebo (P < .001). For patients taking prucalopride, there was a significant reduction in time to first complete spontaneous bowel movement, as well as significant reductions in the use of rescue medication (P < .001).

A rapid response was seen with prucalopride as early as the first week; improvements were maintained throughout 12 weeks of treatment, Shire said in a news release.

New Treatment Option

"As a gastroenterologist, it's important for me to help patients with CIC find a treatment that works well for them. It's exciting to be able to now offer my patients a new treatment option that addresses colonic peristalsis," Brooks Cash, MD, chief of the Division of Gastroenterology, Hepatology, and Nutrition at the University of Texas Health Science Center at Houston, said in the release.

The most common adverse reactions with prucalopride are headache, abdominal pain, nausea, diarrhea, abdominal distension, dizziness, vomiting, flatulence, and fatigue. Overall, discontinuation due to adverse events was low (5% with prucalopride 2 mg once daily vs 3% with placebo).

Cardiovascular safety was evaluated in the double-blind, placebo-controlled and open-label studies and in a retrospective observational study. The results showed no increase in the risk for major adverse cardiovascular events with prucalopride relative to polyethylene glycol.

In clinical trials, suicides, suicide attempts, and suicidal ideation have been reported. A causal association between treatment with prucalopride and an increased risk for suicidal ideation and behavior has not been established.

Clinicians are advised to monitor all patients treated with prucalopride for persistent worsening of depression or the emergence of suicidal ideation. Patients, their caregivers, and family members should alert the healthcare provider to any unusual changes in mood or behavior. Patients should discontinue prucalopride immediately if they experience any of these symptoms.

Prucalopride is contraindicated in patients with a history of hypersensitivity to the drug. It is also contraindicated in patients with intestinal perforation or obstruction due to structural or functional disorder of the gut wall; obstructive ileus; severe inflammatory conditions of the intestinal tract, such as Crohn's disease; ulcerative colitis; and toxic megacolon/megarectum.

Full prescribing information is available online.

The FDA has asked Shire to conduct five postmarketing studies to evaluate the pharmacokinetics, efficacy, and safety of prucalopride in CIC patients aged 6 months to younger than 18 years and in pregnant and lactating women with CIC.

The company expects to launch prucalopride in the United States in 2019.

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