Linaclotide

• Irritable Bowel Syndrome with Constipation (IBS-C)
• Chronic Idiopathic Constipation
• Functional Constipation
• GI Motility Disorders

Linaclotide is a guanylate cyclase-C (GC-C) agonist used for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC). This peptide medication works locally in the intestine to increase fluid secretion and accelerate gastrointestinal transit without significant systemic absorption.

Mechanism of Action

Linaclotide is a 14-amino acid peptide that binds to and activates guanylate cyclase-C (GC-C) receptors on the luminal surface of intestinal epithelial cells. Activation of GC-C increases intracellular and extracellular cyclic guanosine monophosphate (cGMP). Elevated extracellular cGMP activates the cystic fibrosis transmembrane conductance regulator (CFTR), leading to chloride and bicarbonate secretion into the intestinal lumen. This increases intestinal fluid secretion and accelerates gastrointestinal transit, relieving constipation. Additionally, elevated extracellular cGMP may reduce visceral pain signaling, addressing the abdominal pain component of IBS-C.

Available Formulations

Linaclotide is available as oral capsules in 72 mcg, 145 mcg, and 290 mcg strengths. The capsules should be taken on an empty stomach at least 30 minutes before the first meal of the day. Capsules should be swallowed whole; alternatively, they can be opened and the contents mixed with applesauce or water (administered orally or via feeding tube).

Medical Uses

Linaclotide is FDA-approved for the treatment of irritable bowel syndrome with constipation (IBS-C) in adults and for the treatment of chronic idiopathic constipation (CIC) in adults. Clinical trials demonstrated improvement in bowel movement frequency, stool consistency, straining, abdominal pain, bloating, and global IBS symptoms.

Dosing Guidelines

For IBS-C, the recommended dose is 290 mcg once daily. For CIC, the recommended dose is 145 mcg once daily; if tolerated but inadequate response, may increase to 290 mcg once daily. A lower dose of 72 mcg once daily is available for CIC if tolerated. Take at least 30 minutes before the first meal of the day. Stop linaclotide if severe diarrhea occurs; treatment may be restarted at a lower dose after resolution.

Important Safety Information

Linaclotide carries a boxed warning stating it is contraindicated in pediatric patients under 2 years of age due to deaths in neonatal mice caused by dehydration from diarrhea. The medication should be avoided in patients 2-17 years of age. Diarrhea is the most common adverse reaction and can be severe; patients should discontinue if severe diarrhea occurs. The medication may worsen symptoms in patients with mechanical gastrointestinal obstruction.

Drug Interactions

No formal drug interaction studies have been conducted. Linaclotide has minimal systemic absorption, so systemic drug interactions are unlikely. The medication acts locally in the gastrointestinal tract. No significant interactions with commonly used medications are expected.

Special Populations

There are no adequate data on linaclotide use during pregnancy. Animal studies showed no evidence of harm at doses much higher than human doses. Use during pregnancy only if clearly needed. It is unknown whether linaclotide or its metabolites are present in human breast milk. Linaclotide is contraindicated in pediatric patients under 2 years of age and should be avoided in patients 2-17 years of age. Elderly patients do not require dose adjustment. No dose adjustment is needed for renal or hepatic impairment as linaclotide and its metabolites are minimally absorbed.