What is the recommended dose of Ibsrela (tenapanor) for treating constipation-predominant irritable bowel syndrome (IBS-C)?

Ibsrela (Tenapanor) Dosing for IBS-C

The recommended dose of Ibsrela (tenapanor) for treating irritable bowel syndrome with constipation (IBS-C) is 50 mg orally twice daily, taken immediately before breakfast and immediately before dinner. 1

FDA-Approved Dosing Regimen

• Standard dose: 50 mg twice daily in adults 2, 1
• Timing: Take immediately prior to the first meal of the day (breakfast) and immediately prior to dinner 3, 1
• Missed dose: Skip the missed dose and take the next dose at the regular time—do not double up 1

Rationale for BID Dosing

The 50 mg twice-daily regimen was selected based on dose-ranging studies demonstrating superior pharmacodynamic effects compared to once-daily dosing with equivalent total daily doses. 3 This dosing schedule aligns with the drug's mechanism of action as a locally-acting NHE3 inhibitor that requires consistent intestinal exposure to maintain therapeutic effect. 2

Clinical Efficacy at This Dose

The 50 mg BID regimen demonstrated robust efficacy in phase 3 trials:

• FDA responder endpoint: 34.1% with tenapanor vs 21.7% with placebo (RR 0.84; 95% CI 0.79-0.90) 2
• Abdominal pain improvement: Risk ratio 0.81 (95% CI 0.73-0.88), representing a 12.1% absolute risk difference 2
• Complete spontaneous bowel movement response: Risk ratio 0.83 (95% CI 0.77-0.90), representing an 11.3% absolute risk difference 2
• Adequate symptom relief at 12 weeks: 58.1% vs 41.1% with placebo 2

Safety Profile and Common Pitfalls

Diarrhea is the most common adverse event (14.8% vs 2.3% with placebo), but is typically mild to moderate and transient. 2

Critical Safety Considerations:

• Severe diarrhea: Occurs in 2.5% of patients—if this develops, suspend dosing immediately and rehydrate the patient 1
• Discontinuation rate: Only 6.5-6.6% of patients discontinued due to diarrhea 2, 1
• Long-term safety: Tenapanor maintained similar safety profile over ≥52 weeks of treatment 4

Contraindications:

• Absolutely contraindicated in patients <6 years of age due to risk of fatal dehydration observed in neonatal rat studies 1
• Contraindicated in mechanical gastrointestinal obstruction 1
• Avoid use in patients 6 to <12 years of age 1

Guideline Recommendations

The American Gastroenterological Association (AGA) provides a conditional recommendation with moderate certainty evidence for using tenapanor in IBS-C patients. 2 This conditional (rather than strong) recommendation reflects the moderate quality of evidence and the need to balance efficacy against the risk of diarrhea in individual patients.

The British Society of Gastroenterology does not specifically mention tenapanor in their 2021 guidelines, as it focuses on medications more widely available internationally. 2

Drug Interactions

• OATP2B1 substrates (e.g., enalapril): Monitor for signs of reduced efficacy of the concomitant drug and adjust dosage as needed 1
• Tenapanor is minimally absorbed systemically, which significantly reduces the potential for drug-drug interactions 5, 6

Mechanism Supporting This Dosing

Tenapanor inhibits the sodium/hydrogen exchanger isoform 3 (NHE3) on the apical surface of intestinal enterocytes, decreasing sodium and phosphate absorption while increasing water secretion into the intestinal lumen. 2, 3 The drug also demonstrates antinociceptive effects on abdominal pain. 2 Because it is locally acting with minimal systemic absorption, plasma concentrations remain well below the IC50 for NHE3, ensuring action is limited to the gastrointestinal tract. 5