Eluxadoline

Approved Indications:

• Irritable Bowel Syndrome with Diarrhea (IBS-D) in Adults:
  Eluxadoline is indicated for the treatment of adults with IBS-D to reduce the frequency of diarrhea and improve abdominal pain and discomfort.

Off-Label / Clinically Accepted Uses:

• Occasionally used in refractory cases of IBS-D where conventional therapy fails.
• Not recommended for IBS with constipation or mixed bowel habits.

Standard Adult Dosing (Oral):

• Recommended Dose: 100 mg orally twice daily with food.
• Mild Hepatic Impairment: 75 mg orally twice daily.
• Renal Impairment: No adjustment for mild to moderate impairment; use with caution in severe impairment.
• Elderly Patients: No specific dose adjustment, but monitor for adverse effects.

Administration Notes:

• Swallow tablets whole; do not crush, split, or chew.
• Take with food to reduce risk of gastrointestinal adverse events.
• Avoid alcohol during therapy.

Eluxadoline is a mixed opioid receptor modulator with activity as a mu-opioid receptor agonist, delta-opioid receptor antagonist, and kappa-opioid receptor agonist in the gastrointestinal tract. The mu-agonist activity slows intestinal transit and reduces diarrhea, delta antagonism helps reduce risk of constipation and mu-induced adverse effects, and kappa activity may contribute to analgesia. Together, these effects improve stool consistency and reduce abdominal pain in IBS-D without significant central opioid effects at therapeutic doses.

• Absorption: Oral bioavailability ~1%; peak plasma concentration within 1.5–2 hours.
• Distribution: Volume of distribution ~105 L; highly protein-bound (~81%).
• Metabolism: Primarily via CYP3A4-mediated oxidation and glucuronidation (UGT1A1, UGT2B7).
• Elimination: ~0.1% excreted unchanged in urine; fecal excretion is major route.
• Half-Life: ~3–5 hours.
• Onset of Action: Clinical effects generally observed within 1 week.

• Pregnancy: No adequate human data; animal studies show no major teratogenicity. Use only if benefits outweigh risks.
• Lactation: Unknown whether excreted in human milk; avoid breastfeeding during therapy.
• Caution: Use only under clinical supervision in pregnant or nursing women.

• Primary Class: Gastrointestinal agent
• Subclass: Mixed opioid receptor modulator for IBS-D

• Known hypersensitivity to Eluxadoline or excipients
• History of biliary duct obstruction, sphincter of Oddi dysfunction, or pancreatitis
• Severe hepatic impairment
• Alcohol abuse (≥3 alcoholic beverages per day)
• History of severe constipation or gastrointestinal obstruction
• Children and adolescents (<18 years)

• Pancreatitis Risk: Increased in patients without a gallbladder or with heavy alcohol use; monitor for abdominal pain.
• Sphincter of Oddi Spasm: Can occur, particularly in post-cholecystectomy patients.
• Constipation / Bowel Obstruction: Monitor bowel habits; discontinue if severe constipation occurs.
• Hepatic Impairment: Avoid in severe impairment; reduce dose in mild impairment.
• Drug Abuse Potential: Low at therapeutic doses, but caution in patients with history of substance abuse.

Common Adverse Effects:

• Constipation
• Nausea
• Abdominal pain
• Vomiting
• Flatulence

Serious or Rare Adverse Effects:

• Pancreatitis
• Severe constipation leading to bowel obstruction
• Sphincter of Oddi spasm
• Hypersensitivity reactions (rare)

Timing and Severity:

• Most common adverse events occur within first few weeks of therapy; generally mild to moderate.
• Serious events are rare but require immediate discontinuation and medical evaluation.

• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin): Increase Eluxadoline plasma levels; avoid co-administration.
• CYP3A4 Inducers (e.g., rifampin, phenytoin): May reduce efficacy; consider alternative therapy.
• OATP1B1 Inhibitors (e.g., cyclosporine): Increase risk of toxicity; avoid concurrent use.
• Other Opioids / CNS Depressants: Potential additive effects; monitor for CNS depression.
• Alcohol: Avoid; increases risk of pancreatitis and liver injury.

• FDA Updates (2022–2023): Highlighted increased pancreatitis risk in patients without gallbladder; added boxed warning for sphincter of Oddi spasm.
• Guideline Recommendations: IBS-D treatment guidelines (AGA, 2023) recommend Eluxadoline as second-line therapy after loperamide failure, emphasizing careful patient selection and monitoring.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C.
• Humidity & Light: Protect from moisture and light; keep in original container.
• Handling: Do not crush or chew tablets.
• Reconstitution: Not applicable; oral tablets ready for use.