Ibsrela - Drug Monograph

Introduction

Ibsrela (tenapanor) is a novel first-in-class medication approved for the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in adults. Developed by Ardelyx, Inc., this small molecule drug represents a unique approach to managing IBS-C symptoms through its localized action in the gastrointestinal tract.

Mechanism of Action

Tenapanor is a minimally systemic inhibitor of the sodium/hydrogen exchanger isoform 3 (NHE3) located on the apical surface of the small intestine and colon. By inhibiting NHE3, tenapanor reduces sodium absorption from the intestinal lumen, which subsequently increases water retention in the bowel lumen through osmotic effects. This mechanism increases intestinal fluid content and transit, leading to softer stools and more frequent bowel movements. Additionally, tenapanor may reduce abdominal pain by decreasing visceral hypersensitivity through inhibition of TRPV1-dependent rectal pain.

Indications

Ibsrela is indicated for the treatment of Irritable Bowel Syndrome with Constipation (IBS-C) in adults.

Dosage and Administration

• Recommended dosage: 50 mg taken orally twice daily
• Administration: Should be taken immediately before breakfast and dinner
• Special populations:

- Renal impairment: No dosage adjustment necessary for mild to moderate impairment. Not recommended in severe renal impairment (eGFR <30 mL/min/1.73m²) - Hepatic impairment: No dosage adjustment necessary - Geriatric patients: No dosage adjustment necessary - Pediatric patients: Safety and effectiveness not established

Pharmacokinetics

• Absorption: Minimal systemic absorption (approximately 0.02% of administered dose)
• Distribution: Primarily confined to the gastrointestinal tract with negligible systemic distribution
• Metabolism: Not metabolized by cytochrome P450 enzymes
• Elimination: Primarily excreted unchanged in feces (>99%)
• Half-life: Not applicable due to minimal systemic exposure

Contraindications

• Known hypersensitivity to tenapanor or any component of the formulation
• Patients with known or suspected mechanical gastrointestinal obstruction

Warnings and Precautions

• Diarrhea: May cause severe diarrhea. Dose reduction or discontinuation should be considered if severe diarrhea occurs
• Pediatric Risk: Not recommended in children under 6 years due to risk of serious dehydration
• Pregnancy: Use only if potential benefit justifies potential risk to fetus (Category C)
• Lactation: Decision should be made whether to discontinue nursing or discontinue drug
• Electrolyte imbalances: Monitor for potential changes in serum electrolytes

Drug Interactions

• Minimal systemic absorption results in low potential for drug-drug interactions
• May affect absorption of other orally administered medications due to increased intestinal transit time
• No clinically significant interactions with CYP450 substrates, inhibitors, or inducers

Adverse Effects

• Diarrhea (16% vs 4% placebo)
• Abdominal distension (3% vs 1%)
• Flatulence (3% vs 1%)
• Dizziness (2% vs 1%)

• Severe diarrhea (reported in clinical trials)
• Dehydration secondary to diarrhea

Monitoring Parameters

• Bowel pattern and stool consistency
• Hydration status, especially in elderly patients
• Electrolyte levels in patients with prolonged diarrhea
• Abdominal pain and bloating symptoms
• Patient weight if significant diarrhea occurs
• Quality of life measures and treatment response

Patient Education

• Take medication immediately before breakfast and dinner
• Report severe diarrhea, dizziness, or signs of dehydration to healthcare provider
• Maintain adequate fluid intake, especially if experiencing diarrhea
• Do not crush or chew tablets
• Inform healthcare provider of all medications being taken
• Expected benefits may include increased bowel movements and reduced abdominal pain
• Allow several weeks for full therapeutic effect
• Contact healthcare provider if symptoms worsen or persist beyond 4 weeks

References

1. Chey WD, Lembo AJ, Rosenbaum DP. Tenapanor Treatment of Patients With Constipation-Predominant Irritable Bowel Syndrome: A Phase 2, Randomized, Placebo-Controlled Efficacy and Safety Study. Am J Gastroenterol. 2017;112(5):763-774. 2. Brenner DM, Fogel R, Dorn SD, et al. Efficacy, Safety, and Tolerability of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: Results of Two Phase 3 Trials. Am J Gastroenterol. 2021;116(6):1294-1303. 3. Ibsrela [package insert]. Waltham, MA: Ardelyx, Inc.; 2021. 4. FDA Approval: NDA 211725. US Food and Drug Administration. 2019. 5. Rosenbaum DP, et al. Tenapanor: A Minimal-Systemic Inhibitor of Sodium Absorption for the Treatment of IBS-C. Gastroenterology. 2016;150(4):S128-S129.