Prucalopride Approved for Idiopathic Constipation

In December, prucalopride (Motegrity, Shire) received FDA approval for treatment of chronic idiopathic constipation. It is a prokinetic agent that stimulates selective serotonin type 4 receptors, which results in increased peristalsis and gastrointestinal motility. It is approved for use in adult patients.

Efficacy

Prucalopride was approved based on the results of six randomized, double-blind placebo-controlled multicenter clinical trials that included 2,484 adult participants. Treatment lasted 12 weeks in five of the studies and 24 weeks in one study. 

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Eligible participants had a history of chronic constipation (defined as fewer than three spontaneous bowel movements per week that provided a feeling of complete evacuation) and at least one of the following for at least 25% of bowel movements over the previous three months: hard stools, straining at defecation, or a feeling of incomplete evacuation. Patients were not eligible for the studies if constipation could be contributed to another medical condition or medications. All participants less than 65 years of age received 2 mg of prucalopride daily. In five studies, participants older than 65 years were initiated on 1 mg of prucalopride daily. The dose was increased within two to four weeks based on effect. 

Across these studies, 81% of geriatric patients initiated on 1 mg later received the higher dose. During the trials, participants were defined as responders if, over the course of 12 weeks, she or he reported an average of three or more complete spontaneous bowel movements (CSBM) weekly. Overall, more responders across the studies had been given prucalopride than placebo. 

This primary endpoint was achieved with statistical significance in five of the six studies. Participants taking prucalopride could experience improvement of symptoms as early as the first week of therapy and maintained the benefits through week 12. 

Safety

Prucalopride is contraindicated in patients with intestinal obstruction or perforation. The manufacturer includes a warning to immediately discontinue prucalopride if depression worsens or suicidal ideation or behavior occurs. Patients should be counseled to discontinue prucalopride and call their prescriber if these conditions occur.

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The most common adverse effects occurring in study participants included: headache, abdominal pain, nausea, abdominal distension, dizziness, vomiting, flatulence, and fatigue. These adverse effects occurred in both participant groups, but each occurred with greater frequency among participants administered prucalopride. Collectively in the six studies, 5% of participants who were given prucalopride discontinued therapy compared to 3% of participants receiving placebo. The most common adverse reactions leading to discontinuation of therapy were nausea, headache, diarrhea, and abdominal pain. There is insufficient data on use of prucalopride in pregnancy or lactation. Prucalopride is found in breast milk. Its effects on milk production and the child are not known.

Dosing

Prucalopride is available as 1-mg and 2-mg tablets that can be taken with or without food. It is approved for use in adult patients as a once daily 2-mg dose. Patients with severe renal impairment (CrCl<30 mL/min) should take a reduced dose of 1 mg daily. Prucalopride is a substrate of CYP 3A4.

Studies to date have not identified clinically significant interactions with coadministration of other drugs. 

Full Prescribing Information

References

1. Motegrity [package insert]. Lexington, MA: Shire US Inc., December 2018