FDA Approves Linaclotide for Constipation Conditions

Linaclotide is currently the only FDA-approved medication indicated for increasing bowel movements and decreasing abdominal pain in men and women with irritable bowel syndrome with constipation (IBS-C). It has been shown to be efficacious in relieving abdominal pain and constipation in patients with IBS-C, and constipation in those with chronic idiopathic constipation (CIC). The drug is a peripherally-acting agent that activates guanylate cyclase-C (GC-C) on intestinal epithelial cells resulting in increased intracellular and extracellular concentrations of cyclic guanosine monophosphate (cGMP).

Relief of constipation symptoms in IBS-C and CIC is believed to be due to an increase in intracellular cGMP resulting in chloride and fluid secretion through the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel and acceleration of colonic transit. Linaclotide’s effect on reducing abdominal pain in IBS-C is thought to be due to increased extracellular cGMP, which has been shown to decrease firing of sensory nerves within the bowel wall in preclinical animal studies.

Patients with CIC who responded to linaclotide had at least three complete spontaneous bowel movements (CSBMs) per week and an increase in one CSBM for at least 9 out of 12 weeks. The 145 mcg and 290 mcg daily doses showed a statistically significant benefit over placebo; the FDA has approved only the lower dose for CIC. The efficacy of linaclotide was sustained throughout the 12 weeks of the trials.

The dose of 290 mcg per day was approved for the treatment of IBS-C, which is usually differentiated from CIC by the presence of predominant abdominal pain associated with constipation. The significant improvement in CSBMs occurred within the first week of treatment. The decrease in abdominal pain was more gradual and appeared to reach its maximum effect at 8 weeks. The significant effect of linaclotide on abdominal pain may be due to an additional independent effect beyond relief of constipation, but further studies are needed to better understand linaclotide’s effect on abdominal pain.

LIN CHANG, M.D., is co-director of the Oppenheimer Family Center for Neurobiology of Stress and director of the Digestive Health and Nutrition Clinic at the University of California, Los Angeles. She is a consultant for Ironwood Pharmaceuticals and Forest Laboratories and has received grant support from Ironwood Pharmaceuticals.