How to manage diarrhea in patients taking Enhertu (trastuzumab deruxtecan)?

Management of Enhertu-Induced Diarrhea

For patients experiencing diarrhea while taking Enhertu (trastuzumab deruxtecan), initiate loperamide immediately at 4 mg followed by 2 mg every 2-4 hours or after each unformed stool, with a maximum daily dose of 16 mg. 1, 2

Grade-Based Management Algorithm

Grade 1-2 Diarrhea (Uncomplicated)

Uncomplicated diarrhea is defined as grade 1-2 without fever, severe cramping, bloody stools, or signs of dehydration. 1

• Continue Enhertu at the current dose while managing symptoms 1
• Start loperamide 4 mg initially, then 2 mg every 2-4 hours or after each unformed stool (maximum 16 mg/day) 1, 2
• Implement dietary modifications immediately: eliminate all lactose-containing products (except yogurt and firm cheeses), avoid coffee, alcohol, spices, and reduce insoluble fiber intake 1
• Ensure oral hydration with isotonic solutions (1 L/day minimum) 1
• Instruct patients to record stool frequency and report if diarrhea persists >48 hours or worsens 1

Grade 2 Diarrhea Persisting >48 Hours

If diarrhea continues despite maximum loperamide dosing for 48 hours:

• Add codeine 30 mg twice daily (can increase to 60 mg four times daily short-term) 1
• Consider holding Enhertu temporarily 1
• Obtain stool cultures to rule out infectious causes (C. difficile, Salmonella, E. coli, Campylobacter) 1
• Escalate to clinic evaluation rather than telephone management 1

Grade 3-4 Diarrhea (Complicated)

Complicated diarrhea includes any of: moderate-to-severe cramping, nausea/vomiting, fever, bloody stools, signs of dehydration, or diminished performance status. 1

• Hospitalize immediately for aggressive management 1
• Discontinue Enhertu until resolution 1
• Administer IV fluids and correct electrolyte abnormalities, targeting urine output >0.5 mL/kg/h 1
• Continue loperamide at maximum doses (16 mg/day) 1
• Add octreotide 100-150 mcg subcutaneously or IV three times daily; escalate up to 500 mcg three times daily or 25-50 mcg/h continuous IV infusion if needed 1
• Start empiric antibiotics (fluoroquinolone) while awaiting stool cultures 1
• Obtain complete blood count and comprehensive metabolic panel 1
• Evaluate for neutropenic enterocolitis if neutropenic 1

Resuming Enhertu After Diarrhea Resolution

• Once diarrhea improves to grade ≤1 or returns to baseline, consider restarting Enhertu at a reduced dose per prescribing information 1
• Taper and discontinue codeine when restarting Enhertu to avoid constipation 1
• Continue loperamide prophylactically at lower doses if needed

Critical Pitfalls to Avoid

Do not delay loperamide initiation - early intervention prevents progression to severe, complicated diarrhea requiring hospitalization. 1, 3

Do not use loperamide or opioids in grade 3-4 diarrhea with suspected colitis - this can precipitate toxic megacolon or paralytic ileus. 1

Do not exceed 16 mg/day of loperamide - higher doses carry cardiac risks including QT prolongation and serious arrhythmias, particularly in elderly patients or those on QT-prolonging medications. 2

Do not overlook infectious causes - always obtain stool cultures in complicated or persistent diarrhea, as C. difficile and other pathogens require specific antimicrobial therapy. 1

Monitor for dehydration aggressively - HER2-targeted antibody-drug conjugates like Enhertu combined with prior chemotherapy can cause rapid fluid losses leading to prerenal injury. 1

Special Considerations for Enhertu

While specific Enhertu diarrhea data is limited, the management principles follow established chemotherapy-induced diarrhea guidelines. 1 Diarrhea is a common adverse event with HER2-targeted therapies, occurring in up to 71% of patients receiving similar agents. 4 The incidence typically peaks during active treatment and decreases after therapy completion. 4

Budesonide 9 mg once daily may be considered for loperamide-refractory diarrhea without bloody stools, though prophylactic use is not recommended. 1