What is the management of diarrhea associated with the use of afatinib (Gilotrif)?

From the Guidelines

Management of diarrhea from afatinib requires prompt intervention with both non-pharmacological and pharmacological approaches, starting with loperamide at an initial dose of 4 mg followed by 2 mg after each loose stool, not exceeding 16 mg daily, as recommended by the most recent guidelines 1.

Non-Pharmacological Approaches

• Patients should maintain adequate hydration by drinking at least 8-10 glasses of clear fluids daily
• Follow a BRAT diet (bananas, rice, applesauce, toast) while avoiding spicy foods, caffeine, alcohol, and high-fiber foods
• Dietary modifications, such as eliminating all lactose-containing products and high-osmolar dietary supplements, should be considered 1

Pharmacological Approaches

• Loperamide should be started at an initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool, not to exceed 16 mg/day 1
• For persistent grade 2 diarrhea (4-6 stools/day), afatinib dose reduction may be necessary, typically by 10 mg decrements
• Severe diarrhea (grade 3-4, ≥7 stools/day) requires temporary interruption of afatinib until symptoms improve to grade 1 or less, followed by dose reduction upon resumption
• In refractory cases, adding diphenoxylate/atropine or octreotide may be beneficial, as suggested by previous studies 1

Special Considerations

• Patients who are incontinent of stool due to the risk of pressure ulcer formation should use skin barriers to prevent skin irritation caused by faecal material 1
• Dedicated supportive care services may limit hospitalization and allow better control of symptoms 1
• Prophylactic loperamide is not recommended, and early management is crucial as diarrhea typically develops within the first two weeks of treatment and can lead to dehydration, electrolyte imbalances, and treatment discontinuation if not properly controlled 1

From the FDA Drug Label

For patients who develop prolonged Grade 2 diarrhea lasting more than 48 hours or greater than or equal to Grade 3 diarrhea, withhold GILOTRIF until diarrhea resolves to Grade 1 or less and resume GILOTRIF with appropriate dose reduction [see Dosage and Administration (2.3)]. Provide patients with an anti-diarrheal agent (e.g., loperamide) for self-administration at the onset of diarrhea and instruct patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours.

The management of diarrhea from the use of afatinib involves:

• Withholding afatinib until diarrhea resolves to Grade 1 or less
• Resuming afatinib with an appropriate dose reduction
• Providing patients with an anti-diarrheal agent, such as loperamide, for self-administration at the onset of diarrhea
• Instructing patients to continue anti-diarrheal therapy until loose bowel movements cease for 12 hours 2

From the Research

Management of Diarrhea from Afatinib Use

• Diarrhea is a common adverse event associated with afatinib treatment, which can lead to fluid and electrolyte losses, dehydration, electrolyte imbalances, and renal insufficiency 3.
• Patient education, early identification, timely management, and ongoing assessment are crucial in preventing aggravation, afatinib dose reductions, or therapy discontinuation 3.
• A study found that prophylactic loperamide administration was not effective in preventing severe or intolerable diarrhea during afatinib treatment, and adequate dose reduction may be a better approach to manage afatinib-induced diarrhea 4.
• Multimodal prevention using minocycline, topical steroids, and gargling with sodium azulene may be helpful in maintaining compliance with afatinib treatment 4.

Risk Factors for Severe Diarrhea

• Low weight (<45 kg), female sex, and older age (≥60 years) have been identified as major independent risk factors for severe diarrhea in patients treated with afatinib 5.
• A simple risk score based on the count of these risk factors can identify individuals at lowest and highest risk of severe diarrhea, with a C-statistic of 0.65 5.
• Body weight, body mass index, and body surface area have been found to exhibit a prominent non-linear association with the risk of severe diarrhea, where risk increases markedly at the lower range 5.

Treatment Strategies

• Adjusting the dosing regimen of afatinib itself and implementing combination therapy with sitagliptin may be effective approaches to alleviate diarrhea 6.
• Sitagliptin has been found to promote the production of anti-inflammatory factors, increase the expression of intestinal epithelial tight junction proteins, and improve intestinal microbiota, thereby validating its potential as a therapeutic option for managing afatinib-induced diarrhea 6.
• Antidiarrheal agents such as loperamide, diphenoxylate, codeine sulfate, and tinctures of opium can slow motility and increase the absorption of fluids and nutrients, but their use should be tailored according to presumed etiologies and avoided in certain patient populations 7.