Linaclotide (Linzess)

Summary

Linaclotide is an FDA approved once daily oral peptide (Linzess, approved August 2012) for irritable bowel syndrome with constipation (IBS-C) in adults and children 7 and older, chronic idiopathic constipation (long term constipation with no known cause) in adults, and functional constipation in children 2 and older. In two phase 3 trials of about 800 IBS-C patients each, 33.6% to 33.7% met the combined responder endpoint, meaning less abdominal pain plus more complete bowel movements, versus 13.9% to 21.0% on placebo (a dummy capsule), and diarrhea was the main side effect. It is a prescription drug sold at retail pharmacies, not a compounded or research peptide.

What is Linaclotide?

Linaclotide is a guanylate cyclase-C agonist (synthetic 14 amino acid peptide related to bacterial heat stable enterotoxin). It is also known as Linzess, Constella, MD-1100, MM-416775.

How does it work?

Linaclotide binds guanylate cyclase-C on the luminal surface of intestinal epithelial cells. This raises intracellular cyclic GMP, which activates the CFTR ion channel, increasing chloride and bicarbonate secretion into the gut and accelerating transit. Extracellular cyclic GMP is also thought to reduce the firing of visceral pain afferents. The peptide is minimally absorbed and acts locally in the gut.

FDA-approved uses of Linaclotide

Yes. Linzess has been FDA approved since August 2012. The current label covers irritable bowel syndrome with constipation (IBS-C, recurring belly pain with constipation) in adults and children 7 and older, chronic idiopathic constipation (long term constipation with no known cause) in adults, and functional constipation (constipation without an underlying disease) in children 2 and older. It carries a boxed warning, FDA's most serious label warning, against use under age 2 because of serious dehydration. It is a standard prescription drug dispensed at retail pharmacies. [4]

What does the evidence say about Linaclotide?

Four large phase 3 randomized placebo controlled trials support approval. In IBS-C, a 26 week trial (n = 804) and a 12 week trial (n = 800) both showed about 34% combined responders versus 14% to 21% on placebo. In chronic constipation, two 12 week trials (n = 1,276 combined) showed complete spontaneous bowel movement responder rates of 16% to 21% versus 3% to 6% on placebo. Diarrhea occurred in about 20% of treated patients.

Human evidence

Chey 2012 (26 weeks, n = 804): 290 mcg daily produced a combined abdominal pain and complete spontaneous bowel movement responder rate of 33.7% versus 13.9% with placebo. Rao 2012 (12 weeks plus randomized withdrawal, n = 800): 33.6% versus 21.0% responders, with no rebound worsening after withdrawal. Lembo 2011 (two 12 week trials, n = 630 and 642): complete spontaneous bowel movement responder rates of 21.2% and 16.0% on 145 mcg versus 3.3% and 6.0% on placebo. Diarrhea was the most common adverse event, roughly 20% versus 3% to 5%.

Animal evidence

Rodent studies established the guanylate cyclase-C mechanism, increased intestinal fluid secretion and transit, and reduced visceral hypersensitivity. Juvenile mice died from dehydration at doses that were tolerated by adult animals, which is the basis of the pediatric age restriction on the label.

Key studies

Conditions studied

Is Linaclotide legal in the United States?

FDA and compounding status

FDA approved prescription drug (Linzess, approved August 30, 2012 for IBS-C and chronic idiopathic constipation; pediatric functional constipation indication added in 2023). It is commercially available, so it is not eligible for routine compounding and is not on any 503A bulks list. Not a research chemical.

WADA status

Not WADA prohibited. Not named on the current prohibited list. Athletes should still confirm against the list in force for their season.

Regulatory timeline

1. Aug 30, 2012FDA

   FDA approves Linzess (linaclotide) for IBS-C and chronic constipation

   FDA approved linaclotide capsules (Linzess), a guanylate cyclase-C agonist peptide, for irritable bowel syndrome with constipation and chronic idiopathic constipation in adults.

   Regulatory: FDA approvedSource: Drugs@FDA: Linzess (linaclotide) NDA 202811

Full tracker for Linaclotide or the category-wide tracker.

Linaclotide dose on the FDA label

Doses below are quoted from the FDA label for its approved uses, plus the doses used in the pivotal trials where noted. The prescriber sets the dose; PeptideAgent does not recommend doses or protocols.

FDA label (Linzess, DailyMed): adults with IBS-C, 290 mcg orally once daily; adults with chronic idiopathic constipation, 145 mcg once daily, or 72 mcg based on individual presentation or tolerability; children 7 and older with IBS-C, 145 mcg once daily; children 2 and older with functional constipation, 72 mcg once daily. It is taken on an empty stomach at least 30 minutes before a meal at about the same time each day, and the capsule is not crushed or chewed. It is contraindicated under 2 years of age because of a boxed warning for serious dehydration. The phase 3 IBS-C trials used 290 mcg daily.

Routes reported

What are the side effects and interactions of Linaclotide?

Side effects

Interactions

Contraindications

How do people access Linaclotide legally?

Typical cost: List price roughly 500 to 600 USD per month for brand Linzess; most insured patients pay a copay and a manufacturer savings card is offered for commercially insured patients. Prices verified on the last verified date and change often.

• Rules by state
• Verified provider directory

Frequently asked questions

Decisions about starting, stopping, or combining any treatment belong with a licensed clinician who knows your history.

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Sources

Numbered citations above point to these primary sources. PubMed entries link to the indexed abstract.