How to manage diarrhea as a side effect of Zepbound (relugolix)?

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Last updated: May 29, 2025View editorial policy

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From the Guidelines

To manage diarrhea as a side effect of Zepbound, patients should start with oral hydration, dietary modification, and consider taking loperamide at an initial dose of 4 mg, followed by 2 mg after every loose stool, up to a maximum of 16 mg/day, as recommended by the most recent guidelines 1. When experiencing diarrhea, it is essential to stay well-hydrated and adjust your diet to include more bland, low-fiber foods like bananas, rice, toast, and applesauce, while avoiding spicy foods, dairy, caffeine, and high-fat items.

  • Key management strategies include:
    • Oral hydration to prevent dehydration
    • Dietary modifications to reduce symptom severity
    • Loperamide to reduce the frequency of loose stools, with a recommended initial dose of 4 mg, followed by 2 mg after every loose stool, not exceeding 16 mg/day 1
    • Avoiding skin irritation and notifying the treating physician if symptoms persist or worsen If diarrhea persists beyond 2-3 days, worsens, or is accompanied by severe abdominal pain, fever, or blood in stool, it is crucial to contact your healthcare provider immediately, as they may consider temporarily reducing your Zepbound dose or adjusting the timing of dose increases if diarrhea is severe or persistent 1.
  • It is also important to note that gastrointestinal side effects like diarrhea typically improve as your body adjusts to the medication, usually within a few weeks, as tolerance often develops with continued use. However, it is essential to prioritize managing diarrhea to prevent complications and ensure the best possible quality of life while taking Zepbound.

From the FDA Drug Label

The adverse events reported during clinical investigations of loperamide hydrochloride are difficult to distinguish from symptoms associated with the diarrheal syndrome.

The adverse events with an incidence of 1. 0% or greater, which were reported at least as often in patients on loperamide hydrochloride as on placebo, are presented in the table below.

A number of the adverse events reported during the clinical investigations and post-marketing experience with loperamide are frequent symptoms of the underlying diarrheal syndrome (abdominal pain/discomfort, nausea, vomiting, dry mouth, tiredness, drowsiness, dizziness, constipation, and flatulence).

Managing Diarrhea Side Effect of Zepbound (loperamide)

To manage diarrhea side effect of Zepbound, the following steps can be taken:

  • Monitor patients: closely for signs of central nervous system (CNS) toxicity, especially in patients with hepatic impairment 2
  • Adjust dosage: with caution in patients with hepatic impairment, as the systemic exposure to loperamide may be increased due to reduced metabolism 2
  • Report to healthcare provider: if clinical improvement is not observed in 48 hours, or if patient experiences fainting episode, rapid or irregular heartbeat, or becomes unresponsive 2
  • Contact healthcare provider: if patient sees blood in their stools, or if they develop a fever or abdominal distention 2

Note: The FDA drug label does not provide direct guidance on managing diarrhea side effect of Zepbound. The above information is based on the available data on loperamide, which is the active ingredient in Zepbound.

From the Research

Managing Diarrhea Side Effect of Zepbound

To manage diarrhea side effect of Zepbound, the following options can be considered:

  • Loperamide: Studies have shown that loperamide is a safe and effective antidiarrheal for the treatment of acute diarrhea 3, 4, 5. It has been compared with bismuth subsalicylate and found to be more effective in reducing the average number of unformed bowel movements and providing faster relief.
  • Bismuth subsalicylate: Although loperamide has been found to be more effective, bismuth subsalicylate can still be beneficial in preventing and treating infectious diarrhea, including traveler's diarrhea 6. It has been shown to have bacteriostatic/bactericidal effects against a variety of pathogenic gastrointestinal bacteria.

Comparison of Loperamide and Bismuth Subsalicylate

The studies suggest that:

  • Loperamide is more effective than bismuth subsalicylate in reducing the average number of unformed bowel movements and providing faster relief 4, 5.
  • Loperamide is safe and well-tolerated, with few adverse reactions reported 3, 4, 5.
  • Bismuth subsalicylate can be beneficial in preventing and treating infectious diarrhea, including traveler's diarrhea 6.

Treatment Options

Based on the studies, the following treatment options can be considered:

  • Loperamide hydrochloride (Imodium A-D) at a daily dosage limit of 8 mg (40 ml) 5.
  • Bismuth subsalicylate (Pepto-Bismol) at a daily dosage of 4.9 g 5.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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