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

From the Guidelines

Management of diarrhea associated with afatinib requires prompt intervention with loperamide at the first sign of loose stools, with an initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool, not exceeding 16 mg/day, as recommended by the most recent guidelines 1.

Key Considerations

• Patients with grade 1 or 2 diarrhea with no other complicating signs or symptoms may be managed conservatively with oral hydration and loperamide 1.
• For persistent or severe diarrhea (grade 3 or higher), afatinib should be temporarily interrupted until symptoms improve to grade 1 or resolve completely, then resumed at a reduced dose (typically 10 mg lower than the previous dose) 1.
• Dietary modifications can help manage symptoms, including avoiding spicy foods, caffeine, alcohol, and high-fiber foods during episodes.
• Patients should be educated to report diarrhea promptly as it typically occurs within the first two weeks of treatment.
• Afatinib-induced diarrhea results from EGFR inhibition in intestinal epithelial cells, disrupting chloride secretion and mucosal integrity.

Treatment Approach

• Loperamide is the first-line treatment for afatinib-induced diarrhea, with a recommended initial dose of 4 mg followed by 2 mg every 4 hours or after every unformed stool, not exceeding 16 mg/day 1.
• For loperamide-refractory diarrhea, octreotide may be considered, with a starting dose of 500 μg tid sc 1.
• Prophylactic loperamide is not recommended, but having medication readily available before starting afatinib therapy ensures timely management when symptoms appear.

Monitoring and Follow-up

• Patients should be closely monitored for signs of dehydration, electrolyte imbalances, and other complications.
• Regular follow-up appointments should be scheduled to assess the effectiveness of treatment and adjust the dose of afatinib as needed.

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 with the use of afatinib involves:

• Withholding afatinib in patients with prolonged Grade 2 diarrhea or Grade 3 diarrhea until the diarrhea resolves to Grade 1 or less
• Resuming afatinib with an appropriate dose reduction after the diarrhea has resolved
• Providing patients with an anti-diarrheal agent, such as loperamide, 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 with Afatinib

• Afatinib, an irreversible oral ErbB family blocker, is associated with gastrointestinal adverse events, including diarrhea, which can impact a patient's quality of life 3.
• Severe diarrhea can result in fluid and electrolyte losses, leading to dehydration, electrolyte imbalances, and renal insufficiency, highlighting the need for effective management strategies 3.
• Patient education, early identification, timely management, and ongoing assessment are crucial in preventing aggravation, afatinib dose reductions, or therapy discontinuation 3.

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 4.
• 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 4.
• Body weight, body mass index, and body surface area have been found to exhibit a non-linear association with the risk of severe diarrhea, with increased risk at the lower range 4.

Treatment and Management Strategies

• Octreotide has been shown to be more effective than loperamide in controlling diarrhea and eliminating the need for replenishment of fluids and electrolytes in patients with fluorouracil-induced diarrhea 5.
• Multimodal prophylactic treatment, including oral loperamide, prophylactic minocycline, topical medium-class steroids, and gargling with sodium azulene, may be helpful in maintaining compliance with afatinib treatment 6.
• Adjusting the dosing regimen of afatinib and implementing combination therapy with sitagliptin may be effective strategies for alleviating afatinib-induced diarrhea 7.
• 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, validating its potential as a therapeutic option for managing afatinib-induced diarrhea 7.