— In a pivotal trial, treatment with linaclotide doubled weekly spontaneous bowel movements
Ian Ingram, Managing Editor, MedPage Today
June 12, 2023
The FDA approved linaclotide (Linzess) capsules for treating functional constipation in kids 6 years and up, the agency announced on Monday.
Along with data from trials in adults with chronic idiopathic constipation, support for the pediatric approval came from a phase III trial that included 330 children and adolescents ages 6 to 17 years with modified Rome III criteria for functional constipation, a condition with no known cause that is marked by infrequent and hard stools.
In the 12-week trial, treatment with the guanylate cyclase-C agonist at a once-daily dose of 72 mcg significantly increased the frequency of weekly spontaneous bowel movements (SBMs) from baseline, with a twofold improvement compared with placebo (least squares mean change of 2.220 vs 1.050, respectively; P<0.0001), according to topline data released by drugmaker Ironwood Pharmaceuticals last year.
The FDA noted that SBM frequency improved during the first week of treatment and was maintained over the duration of the trial.
Linaclotide also led to improvements in stool consistency, a secondary endpoint, as measured by the 7-point Bristol Stool Form Scale, where the lowest score indicates hard and difficult-to-pass stools and the highest represents liquid bowel movements. At study end, the least squares mean change from baseline reached 1.108 points for the treatment group compared with 0.685 for the placebo group (P=0.0001).
Modified Rome III criteria for functional constipation in the trial included fewer than three SBMs per week along with at least one of the following per week in the 2 months before enrollment: “history of stool withholding or excessive voluntary stool retention”; “history of painful or hard bowel movements”; “history of large diameter stools that may obstruct the toilet”; “presence of a large fecal mass in the rectum”; or “one episode of fecal incontinence per week.”
Diarrhea was the most frequent treatment-emergent adverse event in the linaclotide group (4.3% vs 1.8% of placebo recipients).
Linaclotide should be discontinued in children who experience severe diarrhea, the FDA said, and these patients require rehydratation. The drug’s new labeling contains a boxed warning stating that linaclotide should not be taken by patients under 2 years of age, and notes that linaclotide caused dehydration-related deaths in studies of neonatal mice. The agency added that the drug is contraindicated for patients “with known or suspected mechanical gastrointestinal obstruction.”
Initially approved in 2012, linaclotide is also indicated for treating chronic idiopathic constipation and irritable bowel syndrome with constipation in adults.
Ian Ingram is Managing Editor at MedPage Today and helps cover oncology for the site.