Pharmacology Update
Pharmacology Update
Linaclotide Capsules (Linzess®)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
THE FIRST IN THE CLASS OF GUANYLATE CYCLASE C-RECEPTOR agonists has been approved by the FDA for constipation associated with irritable bowel syndrome and chronic idiopathic constipation. Linaclotide is a synthetic peptide that is chemically related to the endogenous guanylin peptide family. It is marketed by Forest and Inwood Pharmaceuticals as Linzess.
Indications
Linaclotide is indicated for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in adults.1
Dosage
The recommended initial dose is 290 mg once daily for IBS-C and 145 mg for CIC.1 The capsules should be taken on an empty stomach at least 30 minutes before the first meal of the day.
Linaclotide is available as 145 mg and 290 mg capsules.
Potential Advantages
Linaclotide offers a drug with a different mechanism of action for this difficult indication.
Potential Disadvantages
Diarrhea is the most frequent side effect. The discontinuation rate due to diarrhea was 7%-8% compared to 4% for placebo.1,3 Linaclotide should not be used in patients younger than 18 years of age.1
Comments
Linaclotide is a minimally absorbed peptide that is an agonist for guanylate cyclase C receptors. This results in stimulation leading to the secretion of water and electrolytes, which enhances the frequency and ease of bowel movements.1,3 Safety and efficacy of linaclotide for the management of IBS-C were evaluated in two randomized, placebo-controlled, double-blind, 12-week studies in patients who met the Rome II criteria of IBS. This included a mean abdominal pain score of at least 3 on a 0- to 10-point scale, fewer than three complete spontaneous bowel movements (CSBMs) per week, and five or fewer spontaneous bowel movements (SBM) per week. Subjects were randomized to 290 mcg (n = 405, 401) or placebo (n = 395, 403) once daily. Subjects were allowed to continue stable doses of bulk laxatives or stool softeners. Treatment response was combined endpoints of at least a 30% reduction from baseline in mean abdominal pain, at least three CSBMs, and an increase of at least one CSBM from baseline all in the same week for at least 9 out of the first 12 weeks of treatment.
Two studies evaluated the efficacy and safety of linaclotide in CIC in subjects who met the Rome II criteria for functional constipation. These included fewer than three SBMs per week and one of the following symptoms for at least 12 weeks, straining, lumpy or hard stool, and sensation of incomplete evacuation during 25% of bowel movements. Subjects were randomized to 145 mcg (n = 217, 213) daily or placebo (n = 213, 215). The primary endpoint was three or more CSBMs per week and an increase of one or more CSBMs from baseline during at least 9 of 12 weeks. Efficacy responder rates for IBS-C for the combined endpoint (at least 9 out of 12 weeks) were 12.1% and 12.7% for linaclotide and 5.1% and 3% for placebo. These represent a treatment difference (95% confidence interval) of 7% (3.2, 10.9) and 9.7 (6.1, 13.4). For CIC, the response rates were 20.3% and 15.5% compared to 3.3% and 5.6% for placebo. In both IBS-C and CIC, bowel frequency and abdominal pain returned to baseline after drug discontinuation.
Clinical Implications
Constipation is a common gastrointestinal disorder that affects 12% to 19% of the U.S. population.3 Linaclotide is the first of a new class of drugs for the treatment of constipation associated with IBS and CIC. There are currently no comparative studies for currently available agents.
References
1. Linzess Prescribing Information. St. Louis, MO: Forest Pharmaceuticals, Inc.; August 2012.
2. Lembo AJ, et al. N Engl J Med 2011;365:527-536.
3. Lee N, Wald A. Core Evid 2012;7:39-47.
THE FIRST IN THE CLASS OF GUANYLATE CYCLASE C-RECEPTOR agonists has been approved by the FDA for constipation associated with irritable bowel syndrome and chronic idiopathic constipation.Subscribe Now for Access
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