What is Linzess (linaclotide)?

What is Linzess (Linaclotide)?

Linzess (linaclotide) is an FDA-approved, minimally absorbed 14-amino acid peptide medication that works as a guanylate cyclase-C (GC-C) agonist to treat irritable bowel syndrome with constipation (IBS-C) in adults and chronic idiopathic constipation (CIC) in adults and children 6-17 years of age. 1

Mechanism of Action

Linaclotide functions through a dual mechanism that addresses both constipation and abdominal pain:

• Stimulates GC-C receptors on the luminal surface of intestinal enterocytes, increasing intracellular and extracellular cyclic guanosine monophosphate (cGMP) concentrations 2, 1

• Increases intestinal fluid secretion by stimulating chloride and bicarbonate secretion through activation of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel, which accelerates gastrointestinal transit 2, 1

• Reduces visceral pain by increasing extracellular cGMP, which in animal models inhibits colonic nociceptors and decreases the activity of pain-sensing nerves 2, 1

• Minimal systemic absorption with negligible bioavailability, meaning the drug acts locally in the GI tract with concentrations below the limit of quantitation in plasma 1

FDA-Approved Indications and Dosing

For IBS-C in adults: 290 mcg once daily 2, 1

For CIC in adults: 145 mcg or 72 mcg once daily 2, 1

For functional constipation in children 6-17 years: 72 mcg once daily 1

Administration Requirements

• Must be taken on an empty stomach at least 30 minutes before the first meal of the day at approximately the same time each day 1

• Taking immediately after a high-fat breakfast results in looser stools and higher stool frequency compared to the fasted state 1

• Capsules should be swallowed whole, but can be opened and mixed with applesauce or water for patients unable to swallow capsules 1

• If a dose is missed, skip it and take the next dose at the regular time—never take 2 doses at the same time 1

Clinical Efficacy

For IBS-C:

The American Gastroenterological Association provides a strong recommendation with high certainty of evidence for linaclotide in IBS-C 2

• 34.0% of patients met the FDA composite endpoint (improvement in both abdominal pain and complete spontaneous bowel movements) compared to 18.8% with placebo across 4 randomized controlled trials 2

• Improves abdominal pain with 60% of patients achieving ≥30% reduction compared to 48.8% with placebo 2

• Increases complete spontaneous bowel movements (CSBMs) significantly compared to placebo 2

• Improves global symptom relief with 71% achieving adequate relief compared to placebo 2

For CIC:

• Increases CSBMs by 1.37 per week compared to placebo 3, 4

• Increases spontaneous bowel movements by 1.97 per week compared to placebo 3, 4

• Improves stool consistency by a mean difference of 1.25 on the Bristol Stool Scale 3, 4

• Triples responder rates compared to placebo (RR 3.14) 3, 4

• Doubles global relief rates (RR 1.96) 3, 4

Safety Profile and Adverse Effects

Diarrhea is the most common adverse effect, occurring in 16.3% of patients receiving linaclotide compared to 2.3% receiving placebo 2

• Treatment discontinuation due to diarrhea occurs in approximately 3.4% of patients compared to 0.2% with placebo 2

• No serious adverse events or deaths due to diarrhea were reported in clinical trials 2

• The overall certainty of evidence for linaclotide safety and efficacy is rated as HIGH by the AGA 2

Critical Contraindications and Warnings

Absolutely contraindicated in children less than 2 years of age due to risk of severe diarrhea and life-threatening dehydration 1

• In neonatal mice, linaclotide caused deaths due to rapid and severe dehydration from significant fluid shifts into the intestinal lumen 1

Contraindicated in patients with known or suspected mechanical gastrointestinal obstruction 1

• Patients should stop linaclotide and contact their healthcare provider if they experience unusual or severe abdominal pain and/or severe diarrhea, especially with blood in stool 1

Use with caution in patients on diuretics or other medications affecting sodium balance due to potential hyponatremia risk 3

Combination Therapy

Linaclotide can be used as an adjunct to or replacement for over-the-counter laxatives like polyethylene glycol (PEG/Miralax) 4, 5

• Start with OTC laxatives first as initial therapy, then add linaclotide only after an adequate trial provides insufficient relief 4, 5

• Never start both agents simultaneously in treatment-naive patients to avoid excessive bowel response 5

• When combining, take linaclotide on an empty stomach 30 minutes before the first meal, while Miralax can be taken at any time 5

Storage and Handling

• Store at 25°C (77°F) with excursions permitted between 15°C and 30°C 1

• Keep in original container with desiccant—do not subdivide or repackage 1

• Protect from moisture and keep bottles tightly closed in a dry place 1