Linzess (Linaclotide)

December 31, 2012

New molecular entity: FDA approved linaclotide (Linzess, Ironwood Pharmaceuticals and Forest Pharmaceuticals) for the treatment of chronic idiopathic constipation and irritable bowel syndrome (IBS) with constipation in adults.

A guanylate cyclase-C agonist indicated for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation in adults

On August 30, 2012, FDA approved linaclotide (Linzess, Ironwood Pharmaceuticals and Forest Pharmaceuticals) for the treatment of chronic idiopathic constipation and irritable bowel syndrome (IBS) with constipation in adults. Approximately 63 million people are affected by chronic constipation, according to the National Institutes of Health. For those individuals who experience persistent constipation and do not respond to standard therapy, they are diagnosed with chronic idiopathic constipation. IBS affects about 15.3 million people. IBS with constipation, a subtype of IBS, is characterized by abdominal pain and hard or lumpy stools at least 25% of the time and loose or watery stools less than 25% of the time. Linaclotide has been approved with a black-box warning that the drug should not be prescribed for patients 17 years of age and younger due to deaths observed in animal studies.

Efficacy. Linaclotide for the management of chronic idiopathic constipation was evaluated in 2 double-blind, placebo-controlled, randomized, multicenter clinical trials in adults. In the 2 trials, 1,272 patients received linaclotide 145 µg, 290 µg, or placebo once daily for 12 weeks. Results of patients taking linaclotide showed significantly greater improvements compared with placebo in both stool frequency and consistency (increased response by 9.9% to 16.9%). In addition, the 290-µg dose did not offer additional clinical benefit compared with the 145-µg dose. Therefore, linaclotide 145 µg is the recommended dose. Linaclotide for the management of IBS with constipation was also evaluated in 2 double-blind, placebo-controlled, randomized, multicenter trials in adults. In these 2 trials, 1,604 patients were randomly assigned to receive 290 µg of linaclotide or a placebo for 12 weeks. In both trials, patients receiving linaclotide had a significantly higher response rate (increase in response of 7% to 9.7%) in terms of reduced abdominal pain and complete spontaneous bowel movements than placebo-treated patients.

Safety. In the clinical trials for patients with chronic idiopathic constipation, the most common adverse reactions reported in at least 2% of patients receiving 145-µg dose of linaclotide were diarrhea (16%), abdominal pain (7%), flatulence (6%), abdominal distension (3%), upper respiratory tract infection (5%), and sinusitis (3%). Five percent of the linaclotide-treated patients who discontinued therapy did so due to diarrhea compared to 1% in the placebo group. In clinical trials for patients with IBS with constipation, the most common adverse reactions reported in at least 2% of patients receiving 290 µg of linaclotide were diarrhea (20%), abdominal pain (7%), flatulence (4%), abdominal distension (2%), viral gastroenteritis (3%), and headache (4%). Nine percent of patients who received linaclotide discontinued use, most commonly due to diarrhea (5%) and abdominal pain (1%), whereas 3% of the placebo group and less than 1% of all cases withdrew due to diarrhea and abdominal pain. According to a boxed warning, linaclotide should not be used in patients 17 years of age and younger and the drug is contraindicated in pediatric patients up to the age of 6 years of age. In nonclinical studies, young juvenile mice died within 24 hours after receiving 1 or 2 daily oral doses of linaclotide. Although there were no deaths in older juvenile mice, the drug should be avoided in pediatric patients from aged 6 to 17 years, according to the package insert.

Dosing. The recommended dose of linaclotide for chronic idiopathic constipation is 145 µg by mouth once daily, while the dose for IBS with constipation is 290 µg by mouth once daily. It should be taken on an empty stomach, at least half an hour before the first meal of the day. The oral capsule should be swallowed whole, not broken or chewed.