Neratinib Diarrhea Management

Written by: Eric Dallara, RPh
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The purpose is to provide guidance on side effect prevention and management to minimize treatment interruptions. Diarrhea is a common side effect of Neratinib treatment occurring in 95% of patients in the ExteNET trial on the Neratinib arm.1 The majority 93% of the patients experienced diarrhea in the first month of treatment so there is a great need for prevention and close patient monitoring during the first months of therapy.

Background Neratinib is indicated for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab based therapy. Neratinib is an irreversible tyrosine kinase inhibitor of human growth factor receptor 1, 2, and 4 (HER1, HER2, and HER4), as well as epidermal growth factor receptor (EGFR).

PQI Process

Day 1- Initial Patient Counseling

  • Make sure patient has instructions and supply of loperamide and consider colestipol (see figure 1 for dosing). Counsel patient on the importance of diarrhea prophylaxis and remind them that diarrhea occurs in 95% of the patients and grade 3 diarrhea was decreased from 30% in loperamide arm to 10% with the addition of colestipol according to the CONTROL Trial. While the CONTROL Trial reviewed 1 cycle, addressing diarrhea has been seen clinically covering 2 cycles. The average time to diarrhea is 8 days and prophylaxis diarrhea control should continue for a minimum of 2 cycles.
  • Other possible side effects are nausea(43%), abdominal pain(36%), vomiting(26%) and stomatitis (14%).
  • Neratinib should be taken with food and all six tablets(240mg) should be taken as one dose around the same time each day.
  • Patient should be counseled on NOT taking neratinib along with PPIs or H2 antagonists and any other antacid should be given 3 hours prior to neratinib.
  • Neratinib is a major substrate of CYP3A4 so avoid grapefruit juice and other medications that inhibits or increases CYP3A4.
  • Advise patients to call office if diarrhea is uncontrolled with loperamide and colestipol. More than 4 loose stools per day over baseline.

Patient follow-up – Consider following up 1 week after patient therapy initiation and then biweekly in following cycles as needed

  • Assess diarrhea and ask how many loose stools the patient is having per day. Remind them to continue the loperamide and colestipol and report any uncontrollable diarrhea.
  • Verify in your EMR that patient is scheduled for CMP to assess liver function this should be done prior to start and monthly for the first 3 months then every 3 months as clinically indicated.
  • Assess if patient is having uncontrolled nausea or is developing stomatitis.
  • Remind patient that they should not be taking any prescription or over the counter PPIs or H2 antagonists.

Adjustments for Toxicities: Consider discontinuing neratinib if toxicity does not recover to less than or equal to grade 1, for toxicities that result in a treatment delay of more than 3 weeks, or in patients unable to tolerate the 120 mg once daily dose

  • Recommended dose reduction for toxicity:
    • First dose reduction 200mg once daily, second 160mg daily and third 120mg once daily.
  • Diarrhea: Grading
    • Grade 1: Increase of <4 stools/day over baseline
    • Grade 2: Increase of 4 to 6 stools/day over baseline
    • Grade 3: Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; limiting self-care activities of daily living
    • Grade 4: Life-threatening consequences; urgent intervention necessary
  • Diarrhea: Interventions to discuss with medically integrated team

                     *Grade 1, grade 2 (lasting <5 days), or grade 3 diarrhea (lasting <2 days):

  • Adding just antidiarrheal medication and diet
  • Maintain fluid intake of ~2 L.
  • When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose.

                     *Grade 2 diarrhea lasting ≥5 days or grade 3 diarrhea lasting longer than 2 days (despite optimal antidiarrheal management), or any grade diarrhea with complicating features (eg, dehydration, fever, hypotension, renal failure, or grade 3/4 neutropenia):

  • Interrupt treatment. Modify diet; maintain fluid intake of ~2 L.
  • If diarrhea improves to ≤ grade 1 in 1 week or less, resume neratinib at the same dose.
  • If diarrhea improves to ≤ grade 1 in more than 1 week, resume neratinib at the next lower dose.
  • When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose.

                      *Recurrent ≥ grade 2 diarrhea (occurring at 120 mg once daily dose):

  • Permanently discontinue neratinib.

                       *Grade 4 diarrhea:

  • Permanently discontinue neratinib.


  1. NERLYNX [Package Insert]. Los Angeles, CA: Puma Biotechnology, Inc; 2017.
  2. Hurvitz S, Chan A, Iannotti N, et al. Effects of adding budesonide or colestipol to loperamide prophylaxis on neratinib-associated diarrhea in patients with HER2+ early-stage breast cancer: the CONTROL trial. Presented at: 40th Annual San Antonio Breast Cancer Symposium; December 5–9, 2017; San Antonio, TX. Poster P3-14-01.
  3. Chan A, Delaloge S, Holmes FA, et al. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol.2016;17(3):367-377.

Supplemental Information

Important notice: National Community Oncology Dispensing Association, Inc. (NCODA), has developed this Positive Quality Intervention platform. This platform represents a brief summary of medication uses and therapy options derived from information provided by the drug manufacturer and other resources. This platform is intended as an educational aid and does not provide individual medical advice and does not substitute for the advice of a qualified healthcare professional. This platform does not cover all existing information related to the possible uses, directions, doses, precautions, warning, interactions, adverse effects, or risks associated with the medication discussed in the platform and is not intended as a substitute for the advice of a qualified healthcare professional. The materials contained in this platform are for informational purposes only and do not constitute or imply endorsement, recommendation, or favoring of this medication by NCODA, which assumes no liability for and does not ensure the accuracy of the information presented. NCODA does not make any representations with respect to the medications whatsoever, and any and all decisions, with respect to such medications, are at the sole risk of the individual consuming the medication. All decisions related to taking this medication should be made with the guidance and under the direction of a qualified healthcare professional.

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