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DRUG RECORD

 

LINACLOTIDE

OVERVIEW
Linaclotide

 

Introduction

Linaclotide is a minimally absorbed agonist of guanylate cyclase C receptors in the intestine and is used for treatment of chronic constipation and irritable bowel syndrome.  Linaclotide has not been linked to serum enzyme elevations during treatment or to episodes of clinically apparent liver injury.

 

Background

Linaclotide (lin ak’ loe tide) is 14 amino acid peptide that acts as an agonist of the guanylate cyclase C receptors in the intestine.  Activation of this receptor increases cyclic guanosine monophosphate levels which lead to secretion of chloride and bicarbonate into the intestinal lumen, thus increasing fluid secretion and promoting intestinal transit.  Linaclotide acts locally on the luminal side of enterocytes in the upper intestine and is minimally absorbed.  Several clinical trials have shown that linaclotide increases the number of spontaneous bowel movements, improves stool consistency and can alleviate symptoms of chronic constipation including the constipation of irritable bowel syndrome.  Linaclotide was approved for use in the United States in 2012 for irritable bowel syndrome with constipation as well as idiopathic chronic constipation.  Linaclotide is available in capsules of 145 and 290 mcg under the brand name Linzess.  The recommended dose for chronic idiopathic constipation is 145 mcg once daily and for irritable bowel syndrome with constipation is 290 mcg once daily.  It is contraindicated in children below the age of 6 years and is not recommended for use in children below the age of 18 years.  Side effects include diarrhea (~20%), abdominal pain, bloating, flatulence and headache.

 

Hepatotoxicity

In clinical trials, linaclotide therapy was not associated with significant changes in serum enzyme levels or episodes of clinically apparent liver injury.  Since its approval and marketing, there have been no reports of serum aminotransferase elevations or clinically apparent liver injury attributable to linaclotide.  Thus, liver injury from linaclotide must be extremely rare if it occurs at all.

 

Mechanism of Injury

Linaclotide is largely active on the epithelial cells in the intestinal tract and has minimal absorption.  The lack of systemic absorption of low doses used (in micrograms rather than milligrams) probably accounts for the lack of liver injury.

 

Drug Class:  Gastrointestinal Agents, Drugs for Constipation, Irritable Bowel Syndrome Agents

 

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REPRESENTATIVE TRADE NAMES
Linaclotide – Generic, Linzess®

 

DRUG CLASS
Gastrointestinal Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO. MOLECULAR FORMULA STRUCTURE
Linaclotide 851199-59-2 C59-H79-N15-O23-S6 Linaclotide Chemical Structure

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REFERENCES
Linaclotide

 

References updated:  25 April 2014

  1. Zimmerman HJ. Laxatives. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 721-3.  (Expert review of hepatotoxicity of laxatives published in 1999 with discussion of oxyphenisatin and other agents, but not linaclotide).

  2. Sharkey KA, Wallace JL. Treatment of disorders of bowel motility and water flux: anti-emetics; agents used in biliary and pancreatic disease. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1323-50.  (Textbook of pharmacology and therapeutics).

  3. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network(DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, none were attributed to agents used for constipation or irritable bowel syndrome [IBS]).

  4. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none were attributed to gastrointestinal agents, laxatives or drugs for IBS).

  5. Shah E, Kim S, Chong K, Lembo A, Pimentel M. Evaluation of harm in the pharmacotherapy of irritable bowel syndrome. Am J Med 2012; 125: 381-93. PubMed Citation  (Systematic review of adverse side effects of drugs used to treat irritable bowel syndrome including lubiprostone, but not linaclotide).

  6. Lembo AJ, Schneier HA, Shiff SJ, Kurtz CB, MacDougall JE, Jia XD, Shao JZ, et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med 2011; 365: 527-36. PubMed Citation  (Among 1276 patients with chronic constipation treated with linaclotide or placebo for 12 weeks, diarrhea was the most common side effect [14-16% vs 4.7% in controls] and "there were no clinically significant differences in...blood chemistry values" between the two groups).

  7. Rao S, Lembo AJ, Shiff SJ, Lavins BJ, Currie MG, Jia XD, Shi K, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. Am J Gastroenterol 2012; 107: 1714-24. PubMed Citation  (Among 800 patients with constipation predominant IBS treated with linaclotide or placebo for 12 weeks, the most common side effect was diarrhea [20% vs 3.5% with placebo] and there were "no clinically significant differences between the linaclotide and placebo groups in the incidence of abnormal laboratory parameters").

  8. Chey WD, Lembo AJ, Lavins BJ, Shiff SJ, Kurtz CB, Currie MG, MacDougall JE, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012; 107: 1702-12. PubMed Citation  (Among 804 patients with IBS and constipation treated for 12 weeks, pain, bloating and bowel symptoms were improved with linaclotide compared to placebo therapy and side effects were similar except for diarrhea with linaclotide, and "there were no clinically meaningful differences...in the incidence of abnormal laboratory parameters").

  9. Linaclotide (Linzess) for constipation. Med Lett Drugs Ther 2012; 54 (1403): 91-2. PubMed Citation  (Concise summary of the mechanism of action, efficacy and safety of linaclotide for constipation shortly after its approval in the United States; no mention of ALT elevations or hepatotoxicity).

  10. Quigley EM, Tack J, Chey WD, Rao SS, Fortea J, Falques M, Diaz C, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Aliment Pharmacol Ther 2013; 37: 49-61. PubMed Citation  (Reanalysis of controlled trials of linaclotide for constipation predominant IBS [Rao 2012, Chey 2012] using different endpoints; no further discussion of side effects).

  11. Berntgen M, Enzmann H, Schabel E, Prieto Yerro C, Gómez-Outes A, Salmonson T, Musaus J. Linaclotide for treatment of irritable bowel syndrome--the view of European regulators. Dig Liver Dis 2013; 45: 724-6. PubMed Citation  (Review of the efficacy and safety of linaclotide in IBS which led to the approval of its use by the European Medicines Agency).

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OTHER REFERENCE LINKS
Linaclotide
  1. PubMed logoRecent References on Linaclotide

  2. Clinical Trials logoTrials on Linaclotide

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