linaclotide

Action and Spectrum

Actions and Spectrum: 

• Guanylate Cyclase-C (GC-C) Agonist: linaclotide is a selective agonist of the guanylate cyclase-C receptors located on the surface of the intestinal epithelial cells. When linaclotide binds to these receptors, it activates them. 
• cGMP Production: Activation of the guanylate cyclase-C receptors by linaclotide leads to cyclic guanosine monophosphate (cGMP) production within the intestinal cells. 
• Ion Transport Regulation: Increased levels of cGMP in the intestinal cells promote the secretion of chloride ions into the intestinal lumen, increasing fluid secretion. This process helps soften the stool and promote bowel movements. 
• Inhibition of Pain Signaling: linaclotide also has an inhibitory effect on pain signaling in the intestines. It reduces the activation of pain-sensing nerves in the intestinal lining, reducing abdominal pain and discomfort associated with conditions like IBS-C. 

Spectrum of activity: 

• Irritable Bowel Syndrome with Constipation (IBS-C): linaclotide is indicated for treating IBS-C in adults. It helps relieve the symptoms of abdominal pain, bloating, and constipation associated with IBS-C. 
• Chronic Idiopathic Constipation (CIC): linaclotide is also approved for treating chronic idiopathic constipation in adults. It helps increase bowel movements and alleviate constipation symptoms. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

CIC 

Diarrhea (16-22%) 

IBS-C 

Diarrhea (20%)  

1-10% 

IBS-C 

Flatulence (4%) 

Viral gastroenteritis (3%) 

Severe diarrhea (2%) 

Fecal incontinence (<2%) 

Gastroesophageal reflux disease (<2%) 

Abdominal pain (7%) 

Headache (4%) 

Abdominal distension (2%) 

Defecation urgency (<2%) 

Vomiting (<2%)  

CIC 

Flatulence (6%) 

Sinusitis (3%) 

Defecation urgency (<2%) 

Fecal incontinence (<2%) 

Dyspepsia (<2%) 

Viral gastroenteritis (<2%) 

Abdominal pain (7%) 

Upper respiratory tract infection (5%) 

Abdominal distension (1-3%) 

FC 

Diarrhea (4%) 

Frequency not defined 

Abdominal discomfort 

Nausea 

Dehydration  

Post marketing reports 

Angioedema 

Anaphylaxis 

Hematochezia 

Black Box Warning

Black box warning: 

linaclotide is contraindicated in pediatric patients below two years. In nonclinical studies involving neonatal mice, the oral administration of a single clinically relevant adult dose of linaclotide resulted in deaths due to dehydration. 

Contraindication / Caution

Contraindications/caution: 

Contraindications: 

• Pediatric Patients Under 6 Years of Age: linaclotide is contraindicated in patients under 6. The safety and effectiveness of linaclotide in this age group have not been established. 
• Known or Suspected Mechanical Gastrointestinal Obstruction: linaclotide is contraindicated in patients with known or suspected mechanical gastrointestinal obstruction.  

Caution: 

• Severe Diarrhea: linaclotide can cause diarrhea, which can be severe in some cases. If a patient develops severe diarrhea, it is recommended to discontinue linaclotide and evaluate for potential dehydration or electrolyte imbalances. 
• Gastrointestinal Conditions: linaclotide should be used cautiously in patients with known or suspected gastrointestinal disorders such as diverticulitis, toxic megacolon, or gastrointestinal perforation.  
• Renal or Hepatic Impairment: linaclotide has not been specifically studied in patients with renal or hepatic impairment. Caution is advised when using linaclotide in these patients, as the pharmacokinetics and safety profile may be altered. 

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available 

Lactation: Excretion of the drug in human breast milk is unknown 

Pregnancy category: 

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester. 

<b>Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women. 

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.    

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.    

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.    

Category N: There is no data available for the drug under this category 

Pharmacology

Pharmacology: 

• Guanylate Cyclase-C (GC-C) Agonist: linaclotide is a selective agonist of the guanylate cyclase-C receptors located on the surface of the intestinal epithelial cells. When linaclotide binds to these receptors, it activates them. 
• cGMP Production: Activation of the guanylate cyclase-C receptors by linaclotide leads to cyclic guanosine monophosphate (cGMP) production within the intestinal cells. 
• Ion Transport Regulation: Increased cGMP levels in the intestinal cells result in increased secretion of chloride ions into the intestinal lumen, leading to increased fluid secretion. This promotes the softening of stool and enhances bowel movements. 

Pharmacodynamics: 

The pharmacodynamic actions of linaclotide are primarily localized to the gastrointestinal tract, where it acts on the intestinal epithelial cells and the associated signaling pathways. By increasing fluid secretion, enhancing bowel motility, and reducing pain sensitivity, linaclotide helps alleviate constipation symptoms and improve bowel function in conditions like IBS-C and chronic idiopathic constipation (CIC). 

Pharmacokinetics: 

Absorption 

linaclotide is minimally absorbed from the gastrointestinal tract after oral administration. It has poor oral bioavailability, with less than 1% of the administered dose being absorbed systemically. linaclotide remains mainly within the intestinal lumen, exerting its local pharmacological effects. 

Distribution 

linaclotide does not extensively distribute into tissues throughout the body. It remains localized in the gastrointestinal tract, specifically acting on the intestinal epithelial cells. 

Metabolism 

linaclotide undergoes extensive degradation by proteolytic enzymes in the gastrointestinal tract. This metabolism results in the formation of smaller peptide fragments and individual amino acids. linaclotide is not subject to significant systemic metabolism due to its limited absorption. 

Elimination and Excretion 

The metabolites of linaclotide are primarily eliminated via feces. The unchanged drug is excreted in negligible amounts through urine. Since linaclotide mainly acts within the gastrointestinal tract and is minimally absorbed systemically, its excretion primarily occurs by eliminating unabsorbed drugs and metabolites in the feces. 

Adminstartion

Administration: 

linaclotide is usually taken on an empty stomach at least 30 minutes before the day’s first meal. Taking it on an empty stomach helps optimize its absorption and effectiveness. 

The linaclotide capsules should be swallowed whole with a glass of water. Do not chew, crush, or break the capsules before swallowing. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: linaclotide 

Why do we use linaclotide? 

linaclotide is primarily used for the treatment of two gastrointestinal conditions: 

• Irritable Bowel Syndrome with Constipation (IBS-C): linaclotide is approved for managing symptoms associated with IBS-C in adults. IBS-C is a chronic disorder characterized by abdominal pain, discomfort, constipation, or hard stools. linaclotide helps relieve abdominal pain and discomfort, improves bowel movements, and reduces constipation in individuals with IBS-C. 
• Chronic Idiopathic Constipation (CIC): linaclotide is also approved for treating chronic idiopathic constipation in adults. CIC refers to long-term constipation without a known underlying cause. linaclotide helps increase bowel movements, soften stools, and alleviate constipation in individuals with CIC.