Linaclotide

Approved Indications:

• Irritable Bowel Syndrome with Constipation (IBS-C):
  Indicated for the treatment of IBS-C in adults, characterized by recurrent abdominal pain associated with constipation.
• Chronic Idiopathic Constipation (CIC):
  Approved for the treatment of CIC in adults when secondary causes of constipation have been ruled out.

Off-label or Clinically Accepted Use:

• Opioid-Induced Constipation (OIC):
  Occasionally used off-label in adults with OIC unresponsive to conventional laxatives, though not officially approved for this indication.

Route of Administration: Oral

Adults:

• IBS-C:
  290 mcg orally once daily, at least 30 minutes before the first meal of the day.
• CIC:
  145 mcg orally once daily, at least 30 minutes before the first meal.
  A lower dose of 72 mcg once daily may be used in select patients with increased sensitivity or mild symptoms.

Pediatrics:

• Contraindicated in children under 6 years due to risk of life-threatening dehydration.
• Not recommended for patients aged 6 to 17 years because safety and efficacy have not been established.

Elderly:

• No dosage adjustment required. Monitor for dehydration and diarrhea-related complications.

Renal and Hepatic Impairment:

• No dose adjustment necessary. Use with caution due to limited clinical data.

Administration Instructions:

• Capsules should be swallowed whole with water.
• Do not chew or crush.
• If swallowing is difficult, the capsule contents may be mixed with applesauce or water and taken immediately.

Linaclotide is a guanylate cyclase-C (GC-C) agonist that binds to GC-C receptors on the luminal surface of the intestinal epithelium. This activates intracellular cyclic guanosine monophosphate (cGMP) production, which in turn stimulates the secretion of chloride and bicarbonate into the intestinal lumen via cystic fibrosis transmembrane conductance regulator (CFTR) channels. This increases intestinal fluid secretion, softens stool, and enhances gastrointestinal transit. Additionally, extracellular cGMP reduces visceral pain by decreasing the sensitivity of pain-sensing nerves in the gut, contributing to its dual action in relieving both constipation and abdominal pain.

Absorption:

• Minimal to no systemic absorption. Acts locally in the gastrointestinal tract.

Distribution:

• Not systemically distributed due to negligible absorption.

Metabolism:

• Undergoes proteolytic cleavage within the gastrointestinal tract into active and inactive metabolites.

Excretion:

• Excreted primarily in feces. No significant renal elimination.

Onset of Action:

• Symptom relief may occur within 1 week of initiation in most patients.

Bioavailability:

• Negligible; designed for local action.

Half-life:

• Not clinically meaningful due to minimal systemic exposure.

• Pregnancy:
  Animal studies have shown fetal harm at high doses. No adequate data in pregnant women.
  Linaclotide should be used during pregnancy only if clearly necessary.
• Lactation:
  Unknown if linaclotide is excreted in human milk. However, systemic exposure is minimal, and the risk to nursing infants is expected to be low.
  Caution is advised when administering to breastfeeding mothers.
• Recommendation:
  Avoid use during pregnancy unless benefits outweigh risks. Use with caution during lactation.

• Primary Class: Gastrointestinal Agent
• Subclass: Guanylate Cyclase-C (GC-C) Agonist
• Functional Group: Intestinal Secretagogue

• Known hypersensitivity to linaclotide or any of its components
• Pediatric patients under 6 years of age (risk of fatal dehydration)
• Suspected or known mechanical gastrointestinal obstruction

• Pediatric Use Warning:
  Fatal dehydration has occurred in animal studies. Strictly contraindicated in children under 6 years. Not recommended for use in individuals aged 6 to 17 years.
• Severe Diarrhea:
  May cause severe diarrhea leading to dehydration, electrolyte disturbances, or hospitalization. Discontinue if severe diarrhea occurs.
• Abdominal Pain and Bloating:
  Common, especially during early treatment. Usually mild to moderate in severity.
• Use in GI Diseases:
  Use cautiously in patients with known or suspected gastrointestinal diseases, including inflammatory bowel disease.
• Monitoring:
  Monitor hydration status and symptoms, especially in elderly patients or those prone to fluid loss.

Common Adverse Effects (≥2% incidence):

• Gastrointestinal: Diarrhea, abdominal pain, flatulence, bloating
• Others: Headache, fatigue, nausea

Serious Side Effects:

• Severe diarrhea with dehydration
• Fecal incontinence
• Hypokalemia or electrolyte imbalance (secondary to diarrhea)

Rare or Unknown Frequency:

• Allergic reactions (rash, urticaria)
• Gastrointestinal bleeding (very rare)

Onset and Severity:

• Most side effects begin within the first few days of treatment and are dose-dependent.

• Drug-Drug Interactions:
  Linaclotide has minimal systemic exposure and does not significantly interact with other drugs.
• Absorption Interference:
  Severe diarrhea may reduce the absorption of oral medications with a narrow therapeutic index.
• CYP450 Involvement:
  Linaclotide is not metabolized via CYP enzymes and does not induce or inhibit CYP pathways.
• Drug-Food Interaction:
  Taking linaclotide with food may increase gastrointestinal adverse effects. Administer on an empty stomach.
• Drug-Alcohol Interaction:
  No known direct interaction, but alcohol may worsen dehydration and gastrointestinal symptoms.

• FDA Safety Communications:
  Reinforced contraindication in pediatric patients under 6 years due to post-marketing reports of fatal dehydration.
• Guideline Updates:
  Linaclotide remains a recommended first-line therapy for IBS-C and CIC in current American College of Gastroenterology (ACG) and Rome IV guidelines.
• Dose Options:
  Introduction of a lower 72 mcg dose for CIC offers a starting point for patients sensitive to higher doses.

• Storage Temperature: 20°C to 25°C (68°F to 77°F)
• Permitted Range: 15°C to 30°C (59°F to 86°F)
• Humidity Protection: Store in a dry place; protect from moisture.
• Light Protection: Store in the original container with desiccant; protect from light.
• Handling Instructions:
• Keep the bottle tightly closed.
• Do not remove desiccant.
• Do not repackage.
• Keep out of reach of children.