Management of Abemaciclib Associated Diarrhea

Written by: Derek Gyori, PharmD and Julianne Orr, PharmD
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Abemaciclib is an FDA approved Cyclin Dependent Kinase (CDK) 4 and 6 Inhibitor approved for use in hormone receptor (HR) positive and human epidermal growth factor 2 (HER2) negative metastatic breast cancer. Abemaciclib works downstream of the estrogen receptor to halt the progression from the G1 phase to S phase that is a critical step in the replication of cancerous cells.^1-3 Abemaciclib has been studied across multiple lines of therapy for metastatic breast cancer and is FDA-approved in combination with an aromatase inhibitor, fulvestrant, and as a single agent. In addition, these studies have shown a lower risk of neutropenia but an increased risk of diarrhea compared to other approved CDK 4&6 inhibitors.^1,2,3

Background It is imperative that health care professionals understand how to manage agent specific diarrhea to reduce: risk of discontinuing effective therapy, drastic changes in hydration status, and overall quality of life. Although the mechanism of abemaciclib-induced diarrhea is not fully understood, management of diet along with drug therapy remains the standard of care in patients with abemaciclib-associated diarrhea. In clinical trials, abemaciclib associated diarrhea most frequently occurred in the first cycle of treatment, with a median onset between 6 and 8 days. Diarrhea was often managed in the clinical trials using anti-diarrheal agents sparing the need for dosage reductions or interruptions in the majority of the population.^1,2,3

PQI Process

Upon receipt of abemaciclib prescription:

• Screen for appropriate antidiarrheal medication:
  • Loperamide
  • Diphenoxylate/atropine
  • Tincture of opium
• If no antidiarrheal agent present on medication list, encourage patient to pick up over-the-counter loperamide and keep well stocked while taking abemaciclib
• Counsel patient on compliance and anti-diarrheal specific administration and side effects
• Follow-up with patient by phone after the first week of therapy
  • If loperamide alone does not control diarrhea, contact prescriber for diphenoxylate/atropine (or other antidiarrheal agent)
  • If severe diarrhea (≥ 7 stools per day), may require inpatient admission for fluid and electrolyte administration

Diet Recommendations^4,5,6

• Avoid greasy, spicy, or fried food
• Avoid milk, caffeine, alcohol, and high fiber vegetables
• Eat small frequent meals
• R.A.T Diet (Bananas, Rice, Apple Sauce, Toast)
• Drink three or more liters of clear fluid per day (water, clear liquids, soup, sports drinks)

Abemaciclib Dose Modifications

Drug Therapy Recommendations^4,5,6:

• • Loperamide (over-the-counter)
    • Take two caplets (4 mg) followed by one caplet (2 mg) every four hours until diarrhea-free for 12 hours
    • Stop loperamide after no sign of diarrhea for 12 hours
    • Do not exceed 8 caplets (16 mg) per day
      • If diarrhea does not improve during the first 24 hours of taking loperamide, the patient should contact their health care provider.
    • May take up to 12 caplets per day for chemotherapy-induced diarrhea under medical supervision
      • May schedule loperamide around the clock before adding another agent
  • Diphenoxylate/Atropine (Prescription Only)
    • Take 2 tablets (5 mg) three to four times daily (Max of 8 tablets per day)
    • May alternate with loperamide to achieve around the clock coverage
    • Common side effects: dry skin and mucous membranes, tachycardia, urinary retention, hyperthermia
      • Although uncommon, respiratory depression can occur due to the diphenoxylate component
  • Tincture of Opium (Prescription Only)
    • Deodorized tincture of opium 10 mg/mL of morphine
      • Take 0.6 mL (6 mg) in water every 3 to 4 hours
    • Common side effects: CNS depression, drowsiness, urinary retention, constipation, nausea, headache
      • Although uncommon, respiratory depression can occur

Patient Centered Activities:

• Patient Compliance
  • Encourage patients to take loperamide at the onset of a loose, watery stool and every two hours until resolution of diarrhea
  • This medication only needs to be taken as needed for loose, watery stools
• Patient Education
  • Explain abemaciclib associated diarrhea’s median time to onset in the trials was from 6 to 8 days
  • Drink 6-8 (~3 liters) large glasses (water, clear liquids, soup, sports drinks)
  • Instruct patient to call their provider at the first sign of diarrhea
    • If diarrhea hasn’t improved within 24 hours, your doctor may want to reduce the abemaciclib dose

References:

1. Dickler MN, Tolaney SM, Rugo HS et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res 2017; 23(17): 5218-5224.
2. Sledge GW, Toi M, Neven P, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol 2017; 35:2875-2884.
3. Goetz, MP, Toi M, Campone M, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol 2017; 35:3638-3646.
4. National Comprehensive Cancer Network. Palliative Care (Version 1.2018). https://www.nccn.org/professionals/physician_gls/pdf/palliative.pdf. Accessed May 16, 2018.
5. Rangwala F, Zafar SY, Abernathy AP. Gastrointestinal symptoms in cancer patients with advanced disease: new methodologies, insights, and a proposed approach. Curr Opin Support Palliat Care 2012; 6:69-76.
6. Richardson G, Dobish R. Chemotherapy induced diarrhea. J Oncol Pharm Practice 2007; 13:181-198.

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