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Generic Name: Linaclotide
Class: GI Drugs, Miscellaneous
Chemical Name: Cyclic (1-6),(2-10),(5-13)-tris(disulfide) l - cysteinyl - l - cysteinyl - l - α - glutamyl - l - tyrosyl - l - cysteinyl - l - cysteinyl - l - asparaginyl - l - prolyl - l - alanyl - l - cysteinyl - l - threonylglycyl - l - cysteinyl - l - tyrosine
Molecular Formula: C59H79N15O21S6
CAS Number: 851199-59-2


  • Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6–17 years of age.1 Single, clinically relevant, oral adult dose caused deaths in young juvenile mice.1 (See Pediatric Use under Cautions.)


Guanylate cyclase-C (GC-C) agonist; stimulates secretion of chloride and bicarbonate into intestinal lumen, which increases intestinal fluid and accelerates intestinal transit.1 12 13

Uses for Linzess

Irritable Bowel Syndrome with Constipation

Symptomatic treatment of irritable bowel syndrome (IBS) with constipation in adults.1 2 3 4 6

Chronic Idiopathic Constipation

Symptomatic treatment of chronic idiopathic constipation in adults.1 5

Linzess Dosage and Administration


Oral Administration

Administer orally on an empty stomach, at least 30 minutes prior to first meal of the day.1

Swallow capsules whole; do not break or chew.1



Irritable Bowel Syndrome with Constipation

290 mcg once daily.1

Chronic Idiopathic Constipation

145 mcg once daily.1

Higher dosage (290 mcg daily) not associated with additional clinical benefit.1 14

Special Populations

Hepatic Impairment

No dosage adjustments needed.1

Renal Impairment

No dosage adjustments needed.1

Geriatric Patients

No specific dosage recommendations.1

Cautions for Linzess


  • Infants and children <6 years of age.1 (See Pediatric Use under Cautions.)

  • Known or suspected mechanical GI obstruction.1



Pediatric Risk

Lethality reported in young juvenile mice.1 Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6–17 years of age.1 (See Pediatric Use under Cautions.)

Other Warnings/Precautions


Severe diarrhea reported in 2% of patients.1 If severe diarrhea occurs, interrupt or discontinue treatment.1

Specific Populations


Category C.1


Not known whether distributed into milk; although plasma concentrations not measurable at recommended dosages, use caution.1

Pediatric Use

Contraindicated in infants and children <6 years of age; avoid use in children and adolescents 6–17 years of age.1 Safety and efficacy in pediatric patients not established, and deaths reported in juvenile mice 1–3 weeks of age (approximately equivalent to infants <2 years of age).1

Deaths in young juvenile mice occurred after 1 or 2 doses of 10 mcg/kg given once daily beginning on postnatal day 7, single oral doses of 100 mcg/kg on day 14, and single oral doses of 600 mcg/kg on day 21.1 15

No deaths reported in juvenile mice 6 weeks of age (approximately equivalent to adolescents 12–17 years of age) receiving linaclotide 20,000 mcg/kg daily for 28 days.1 No data available for mice >3 to <6 weeks of age.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.1

Hepatic Impairment

Not studied, but hepatic impairment not expected to affect metabolism or clearance.1

Renal Impairment

Not studied, but renal impairment not expected to affect clearance.1

Common Adverse Effects

Diarrhea,1 2 3 5 abdominal pain,1 2 3 5 flatulence,1 2 3 abdominal distension,1 2 3 5 viral gastroenteritis,1 3 headache,1 2 3 upper respiratory tract infection,1 5 sinusitis.1 5

Interactions for Linzess

Does not interact with CYP isoenzymes in vitro.1

Not a substrate or inhibitor of P-glycoprotein (P-gp).1

No formal drug interaction studies to date.1 However, systemic interactions with other drugs and interactions with highly protein-bound drugs unlikely.1 (See Pharmacokinetics.)

Linzess Pharmacokinetics



Minimally absorbed; low systemic bioavailability following oral administration.1 7


Administration immediately after a high-fat breakfast resulted in looser stools and higher stool frequency.1

Plasma Concentrations

At recommended dosages, plasma concentrations are below measurable levels.1



Expected to be minimally distributed to tissues.1



Metabolized by carboxypeptidase A in GI tract;1 7 parent drug and active metabolite are proteolytically degraded in intestinal lumen to smaller peptides and amino acids.1 7

Elimination Route

3–5% of orally administered dose excreted in feces as active peptide, mainly as active metabolite.1 7

Special Populations

Hepatic impairment: Not studied; not expected to affect metabolism or clearance.1

Renal impairment: Not studied; not expected to affect clearance.1





25°C (may be exposed to 15–30°C).1

Keep in original container, tightly closed and protected from moisture.1 Do not remove desiccant from container.1 Do not subdivide or repackage.1


  • Binds to GC-C receptor on luminal surface of intestinal epithelium.1 2 3 4 5 7 13 Stimulation of GC-C causes increased concentrations of cyclic guanosine monophosphate (cGMP), which activates the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel leading to secretion of chloride and bicarbonate into intestinal lumen; results in increased intestinal fluid and accelerated intestinal transit.1 2 3 4 5

  • Changes stool consistency and increases stool frequency.1

  • In animals, causes decreased visceral hyperalgesia and abdominal pain; effect thought to be mediated by activation of GC-C.1 7 8 9 10 Mechanism(s) of abdominal pain relief in patients with IBS with constipation not fully elucidated.11

Advice to Patients

  • Importance of reading patient information (medication guide) provided by the manufacturer.1

  • Importance of keeping linaclotide out of reach of children.1 Linaclotide may harm pediatric patients; must not be given to children <6 years of age and should not be given to those 6–17 years of age.1 (See Pediatric Use under Cautions.)

  • Diarrhea may occur; importance of discontinuing linaclotide and notifying clinician if diarrhea becomes severe.1

  • Abdominal pain may occur; importance of seeking immediate medical attention if unusual or severe abdominal pain occurs, especially if associated with hematochezia or melena.1

  • Importance of taking linaclotide once daily on an empty stomach.1 Swallow capsule whole; do not break apart or chew.1

  • Importance of storing linaclotide in the original container, protected from moisture; do not remove desiccant from container and do not repackage.1

  • If a dose is missed, omit the missed dose and take the next dose at the regularly scheduled time.1 Do not take 2 doses at the same time.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.



Dosage Forms


Brand Names




145 mcg


Forest, (comarketed by Ironwood)


290 mcg


Forest, (comarketed by Ironwood)

AHFS DI Essentials. © Copyright, 2016, American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

Date published: May 22, 2014
Last reviewed: May 22, 2014
Date modified: February 08, 2016


1. Forest Pharmaceuticals, Inc. and Ironwood Pharmaceuticals, Inc. LINZESS (linaclotide) prescribing information. St. Louis, MO; 2013 Aug.

2. Rao S, Lembo AJ, Shiff SJ 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; quiz p.1725. [PubMed 22986440]

3. Chey WD, Lembo AJ, Lavins BJ 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 22986437]

4. Quigley EM, Tack J, Chey WD 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 23116208]

5. Lembo AJ, Schneier HA, Shiff SJ et al. Two randomized trials of linaclotide for chronic constipation. N Engl J Med. 2011; 365:527-36. [PubMed 21830967]

6. Rao SS, Quigley EM, Shiff SJ et al. Effect of Linaclotide on Severe Abdominal Symptoms in Patients with Irritable Bowel Syndrome with Constipation. Clin Gastroenterol Hepatol. 2013; :. [PubMed 24075889]

7. Busby RW, Kessler MM, Bartolini WP et al. Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. J Pharmacol Exp Ther. 2013; 344:196-206. [PubMed 23090647]

8. Eutamene H, Bradesi S, Larauche M et al. Guanylate cyclase C-mediated antinociceptive effects of linaclotide in rodent models of visceral pain. Neurogastroenterol Motil. 2010; 22:312-e84. [PubMed 19706070]

9. Silos-Santiago I, Hannig G, Eutamene H et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. Pain. 2013; 154:1820-30. [PubMed 23748116]

10. Castro J, Harrington AM, Hughes PA et al. Linaclotide Inhibits Colonic Nociceptors and Relieves Abdominal Pain via Guanylate Cyclase-C and Extracellular Cyclic Guanosine 3',5'-Monophosphate. Gastroenterology. 2013; 145:1334-1346.e11. [PubMed 23958540]

11. Brierley SM. Guanylate cyclase-C receptor activation: unexpected biology. Curr Opin Pharmacol. 2012; 12:632-40. [PubMed 23131468]

12. Bryant AP, Busby RW, Bartolini WP et al. Linaclotide is a potent and selective guanylate cyclase C agonist that elicits pharmacological effects locally in the gastrointestinal tract. Life Sci. 2010; 86:760-5. [PubMed 20307554]

13. Busby RW, Bryant AP, Bartolini WP et al. Linaclotide, through activation of guanylate cyclase C, acts locally in the gastrointestinal tract to elicit enhanced intestinal secretion and transit. Eur J Pharmacol. 2010; 649:328-35. [PubMed 20863829]

14. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202811Orig1s000: Medical review(s). From FDA website.

15. US Food and Drug Administration. Center for Drug Evaluation and Research. Application number 202811Orig1s000: Pharmacology review(s). From FDA website.