19

September

Neratinib (Nerlynx®) Diarrhea Management

Written by: Eric Dallara, RPh, New England Cancer Specialist
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Description:  Diarrhea is the main toxicity of neratinib treatment occurring in 95% of patients in the ExteNET trial on the Neratinib arm in which antidiarrheal prophylaxis was not protocol specified.1  Various prevention and treatment strategies for diarrhea have been studied and will be discussed in this PQI.

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. The majority (95%) of patients experienced diarrhea in the first month of treatment in ExteNET.  Median time to onset of any grade diarrhea is 2 days (8 days for Grade 3) and median cumulative duration of diarrhea was 59 days (5 days for Grade 3). The Phase 2 CONTROL trial was designed to investigate various approaches to preventing and managing diarrhea in patients on neratinib, including various anti-diarrheal combinations, as well as a dose escalation arm. Mature data is available for budesonide and colestipol; interim data are available for dose escalation in Phase 2 CONTROL trial.4 All preventative strategies from the CONTROL trial reduced the incidence, duration, and severity of diarrhea, and also reduced neratinib discontinuation when compared to the pivotal ExteNET trial.

PQI Process: Upon receipt of neratinib prescription:

  • Consider dose escalation based on data from CONTROL trial (see supplemental information for dosing)
  • Diarrhea Prophylaxis – Diarrhea occurs in 95% of the patients without prophylaxis protocol
    • Begin prophylaxis with the first dose or neratinib and continue for 2 cycles depending on the regimen selected and the patient response
    • Ensure patient has instructions and supply of loperamide and consider colestipol or budesonide (see Supplemental Information for dosing)
    • The clinician should exercise his/her best professional judgment in making recommendations for interventions for individual patients
    • Identify drug-drug interactions and side effect profiles of loperamide, colestipol, and budesonide when making clinical recommendations
    • Consider weekly assessment of diarrhea throughout the first 2 cycles
  • Drug-Drug Interactions
    • Avoid concomitant use of PPIs
    • If H2-antagonists must be used, administer neratinib 2 hours before or 10 hours after
    • Other antacids (Tums, Maalox) should be separated by at least 3 hours
  • Verify in EMR that patient is scheduled for CMP to assess liver function
    • Consider monthly CMP for the first 3 months then every 3 months as clinically indicated

 

Patient Centered Activities:

  • Neratinib should be taken with food and around the same time each day
    • Dose escalation – Take three tablets (120 mg) daily for 7 day, then four tablets (160 mg) daily for 7 days, then six tablets (240 mg) daily
    • Initiation without escalation – Take six tablets (240 mg daily) with loperamide during the first 56 days, then loperamide as needed to maintain daily bowel movements
  • Maintain adequate oral hydration throughout treatment unless otherwise indicated
  • Counsel on other possible side effects
    • Diarrhea (95%)
      • Availability of a voucher for 3-months of anti-diarrheal medication at no charge from the manufacturer
      • Advise patients to call office if diarrhea is uncontrolled with anti-diarrheal regimen (more than 4 loose stools per day over baseline)
    • Nausea(43%)
    • Abdominal pain(36%)
    • Vomiting(26%)
    • Stomatitis (14%)
  • Financial Assistance:
  • 3-month voucher available for anti-diarrheal agents
  • Traditional financial assistance for high medication costs available through PumaPatientLynx

References:

  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. Martin M, Holmes FA, Ejlertsen B, et al. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. Dec 2017;18(12):1688-1700. https://www.ncbi.nlm.nih.gov/pubmed/29146401.
  4. Barcenas CH, Hurvitz SA, Di Palma J, et al. Effect of prophylaxis on neratinib-associated diarrhea and tolerability in patients with HER2+ early-stage breast cancer: Phase II CONTROL trial. Presented at the American Society of Clinical Oncology (ASCO) Annual Meeting. May 31-June 4, 2019; Chicago, IL. J Clin Oncol. 2019;37:(suppl; abstr 548). https://bit.ly/2Xu86DO.

Supplemental Information:

Dosing Regimens from CONTROL study:

Loperamide:·      4 mg TID days 1-14, then 4 mg BID days 15-56
Budesonide·      9 mg/day for 1 cycle

·      + loperamide 4 mg TID days 1-14, then 4 mg BID days 15-56

Colestipol·      2 gm BID for 1 cycle + loperamide PRN or

·      + loperamide 4 mg TID days 1-14, then 4 mg BID days 15-28

Neratinib·      120 mg/day on days 1–7, then 160 mg/day on days 8–14,
then 240 mg/day through day 364

or

·      160 mg/day on days 1–14, then 200 mg/day on days 15–28,
then 240 mg/day through day 364

 

Dose Escalation Regimen:

  • 160 mg (4 tablets) daily days 1-14
  • 200 mg (5 tablets) daily days 15-28
  • 240 mg (6 tablets) daily days 29+

Note: Loperamide was given as needed in this arm of the CONTROL study

 

Dosage Adjustment for Diarrhea:

Grade 1 or 2 (<5 days) or Grade 3 (<2 days)

  • Maximize use of antidiarrheal agents and assess diet and aggravating substances
  • When diarrhea has improved to ≤ grade 1 or baseline, initiate loperamide 4 mg with each subsequent neratinib dose

Grade 2 (>5 days) or Grade 3 (>2 days) or any grade with complicating features of 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 or more occurring at 120 mg once daily dose, or, Grade 4 diarrhea:

  • Permanently discontinue neratinib
Important notice: 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.
Victoria

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