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ABEMANAS

Cancer Type: Breast  Intent: Palliative
Regimen Category: Evidence-Informed
Drugs Used:
abemaciclib (Unfunded),
Funding:
ODB Limited Use
    anastrozole - For the treatment of metastatic breast cancer in hormone receptor positive post-menopausal women
A - Regimen Name

ABEMANAS Regimen
Abemaciclib-Anastrozole


Disease Site
Breast

Intent
Palliative

Regimen Category
Evidence-Informed :

Regimen is considered appropriate as part of the standard care of patients; meaningfully improves outcomes (survival, quality of life), tolerability or costs compared to alternatives (recommended by the Disease Site Team and national consensus body e.g. pan-Canadian Oncology Drug Review, pCODR).  Recommendation is based on an appropriately conducted phase III clinical trial relevant to the Canadian context OR (where phase III trials are not feasible) an appropriately sized phase II trial. Regimens where one or more drugs are not approved by Health Canada for any indication will be identified under Rationale and Use.


Rationale and Uses

For treatment of HR+/HER2- advanced breast cancer in patients who were previously treated with endocrine therapy.


Supplementary Public Funding

anastrozole
ODB Limited Use (anastrozole - For the treatment of metastatic breast cancer in hormone receptor positive post-menopausal women)

 
B - Drug Regimen

abemaciclib
150 mg PO BID
(This drug is not currently publicly funded for this regimen and intent)
anastrozole
1 mg PO Daily
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C - Cycle Frequency

CONTINUOUS TREATMENT

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended

 
E - Dose Modifications

Doses should be modified according to the protocol by which the patient is being treated. 

Dosage with toxicity

Dose Level Abemaciclib Dose (mg BID)
0 150
-1 100
-2 50
-3 Discontinue

 

 

Toxicity

Grade

Abemaciclib Action

Anastrozole Action 
Hematologic* Grade 3 Hold until ≤ grade 2; resume at same dose. No adjustment required
Grade 4 or recurrent grade 3 Hold until ≤ grade 2; resume at 1 dose level ↓.
Diarrhea** Grade 2

If no resolution to ≤ grade 1 within 24 hours, hold until resolution; resume at same dose.

Not applicable 
Grade 2 that persists/recurs after resumption at the same dose (despite maximal supportive measures) Hold until ≤ grade 1; resume at 1 dose level ↓.
≥ Grade 3 or requires hospitalization Hold until ≤ grade 1; resume at 1 dose level ↓.
Interstitial lung disease (ILD)/ Pneumonitis Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures) Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓. Not applicable
Grade 3 or 4 Discontinue
Hepatotoxicity Persistent or recurrent grade 2 or grade 3 (ALT, AST >5 to 20 times ULN) without increase in total bilirubin >2 times ULN Hold until recovery to baseline or grade 1; resume at 1 dose level ↓. Refer to “hepatic impairment” table below
AST and/or ALT >3 times ULN with total bilirubin >2 times ULN (in the absence of cholestasis) Discontinue
Grade 4 (ALT, AST >20 times ULN) Discontinue
Hypercalcemia ≥ Grade 3 Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓. Hold; discontinue if recurs
All other non-hematologic toxicities Persistent or recurrent grade 2 toxicity that does not resolve to baseline or grade 1 within 7 days (despite maximal supportive measures) Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓. Not applicable 
≥ Grade 3 Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓.

*If blood cell growth factors are required, hold abemaciclib for at least 48 hours after the last growth factor dose and until toxicity resolves to ≤ grade 2; resume at the next lower dose (unless already reduced due to the toxicity that required the growth factor). Growth factor use is as per current local guidelines.

**At the first sign of loose stools, begin management with antidiarrheal agents (i.e. loperamide) and increase oral fluid intake.



Hepatic Impairment

Hepatic Impairment Abemaciclib Dose Anastrozole Dose
Mild or moderate impairment (Child-Pugh class A or B) No dosage adjustment necessary. No dosage adjustment necessary.
Severe impairment (Child-Pugh class C) Reduce the abemaciclib frequency to once daily. Not been studied, use with caution.

 


Renal Impairment

Renal Impairment Abemaciclib Dose Anastrozole Dose
Mild or Moderate (CrCl ≥ 30 mL/min) No dosage adjustment necessary. No dosage adjustment necessary.
Severe (CrCl < 30 mL/min); ESRD Has not been studied

 


Dosage in the Elderly

No dosage adjustment is required for abemaciclib and anastrozole.  Patients ≥65 years of age reported more hematologic adverse events, hypokalemia (including grade 3), hypocalcemia, grade ≥3 infections, decreased appetite, and increased blood creatinine compared to younger patients in a subgroup analysis from clinical studies.

 

Dosage based on Ethnicity 

Higher incidences of increased ALT and AST and neutropenia have been reported in East Asian patients on abemaciclib compared to Caucasian patients in clinical trials.  No dose adjustment based on race is required for abemaciclib and anastrozole.


 
F - Adverse Effects

Refer to abemaciclib, anastrozole drug monograph(s) for additional details of adverse effects


Very common (≥ 50%)

Common (25-49%)

Less common (10-24%)

Uncommon (< 10%),

but may be severe or life-threatening

  • Diarrhea
  • Myelosuppression ± infection
  • Fatigue
  • Nausea, vomiting
  • Menopausal symptoms
  • Musculoskeletal pain
  • Alopecia
  • Anorexia, weight loss
  • Creatinine increased
  • Headache
  • Mood changes
  • ↑ LFTs
  • Constipation
  • Cough, dyspnea
  • Rash, pruritus (May be severe)
  • Dizziness
  • Hypertension
  • Mucositis
  • Flu-like symptoms
  • Osteoporosis
  • Dry skin
  • Dysgeusia
  • Edema - limbs
  • Insomnia
  • Lymphedema

 

  • Cardiotoxicity
  • Cardiac ischemia
  • Arterial / venous thromboembolism
  • Hypersensitivity
  • Nephrotoxicity
  • Tumour flare
  • Endometrial cancer
  • Pneumonitis
  • Vasculitis
  • Osteonecrosis of jaw
  • Paresthesia
 
G - Interactions

Refer to abemaciclib, anastrozole drug monograph(s) for additional details


  • CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit); Avoid co-administration of abemaciclib with strong CYP3A4 inhibitors. Use caution when co-administered with moderate or weak CYP3A inhibitors. If co-administration with a CYP3A inhibitor is unavoidable, reduce abemaciclib dose to 50 mg twice daily* (based on a 150 mg or 200 mg twice daily starting dose) when combined with strong or moderate CYP3A4 inhibitors. If a CYP3A inhibitor is discontinued, increase the abemaciclib dose (after 3-5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor.

    *When combined with clarithromycin, diltiazem or verapamil, abemaciclib dose should be reduced to 100 mg twice daily.

  • CYP3A4 inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc.); Avoid co-administration of abemaciclib with strong CYP3A4 inducers. Use with caution when co-administered with moderate or weak CYP3A4 inducers.

  • OCT2, MATE1, MATE2 substrates (i.e. metformin); Caution with co-administration of abemaciclib with OCT2, MATE1, MATE2 substrates

  • Tamoxifen; Do not co-administer anastrozole and tamoxifen since no efficacy or safety benefit.

  • Estrogen-containing herbals, estrogen; Avoid co-administration of anastrozole and estrogen-containing herbals or estrogen.

 
H - Drug Administration and Special Precautions

Refer to abemaciclib, letrozole drug monograph(s) for additional details


Administration

Abemaciclib

  • Abemaciclib tablets should be swallowed whole (do not chew, crush, or split tablets before swallowing). Tablets should not be ingested if they are not intact.

  • Abemaciclib doses may be taken with or without food and should be administered at approximately the same times every day.

  • Avoid fruit or juice from grapefruit, Seville oranges or starfruit.

  • If a dose is missed or vomited, the next dose should be taken at the scheduled time. The patient should not take 2 doses at the same time to make up for the missed dose.

  • Store at room temperature (15°C to 30°C).


Anastrozole

  • Swallow whole with a glass of water at the same time each day.

  • Missed dose should be taken as soon as possible, but only if there are at least 12 hours before the next dose is due.
     


Contraindications

  • Patients who are hypersensitive to abemaciclib or anastrozole or to any ingredient in the formulation or component of the container.

  • Pregnancy/breastfeeding is contraindicated with anastrozole. 
     


Other Warnings/Precautions

  • Use of formulations containing lactose should be carefully considered in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.
  • There are no data regarding abemaciclib safety or efficacy in patients with prior exposure to other CDK 4/6 inhibitors.

  • Estrogen should not be co-administered with anastrozole.

  • Use anastrozole with caution in patients with known osteoporosis or risk factors for osteoporosis, in patients with pre-existing cardiovascular disorders, severe liver or renal impairment.

  • Anastrozole has not been studied in patients with brain, leptomeningeal or pulmonary lymphangitic disease.

  • Anastrozole is not recommended for use in premenopausal women as safety and efficacy have not been established.

 

Pregnancy/Lactation

  • Abemaciclib is not recommended for use in pregnancy.  Adequate contraception should be used by both sexes during treatment, and for at least 3 weeks after the last dose.  

  • Anastrozole is contraindicated in pregnancy.

  • Breastfeeding is not recommended during abemaciclib treatment and for at least 3 weeks after the last dose. 

  • Anastrozole is contraindicated in lactating women.

  • Fertility Effects:

    • Abemaciclib: Unknown

      • In animal studies, no effects on female reproductive organs were observed. However, cytotoxic effects to the male reproductive tract in rats and dogs indicate that abemaciclib may impair fertility in males

    • Anastrozole:  Likely. 

      • Observed in animal studies

      • Oral administration of anastrozole to female rats produced a high incidence of infertility. These effects were related to the pharmacology of the compound and were completely reversed after a 5-week compound withdrawal period.

 
I - Recommended Clinical Monitoring

Recommended Clinical Monitoring

  • CBC; Baseline, every two weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.

  • Liver function tests; Baseline, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated.

  • Creatinine; Baseline and as clinically indicated

  • Bone mineral density for patients at risk; Baseline and routine

  • Clinical toxicity assessment for signs and symptoms of venous thrombosis, infections, musculoskeletal, estrogen withdrawal symptoms, dermatological, edema, cardiovascular, gastrointestinal, respiratory and genitourinary effects and fatigue; At each visit

  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

  • Cholesterol and lipid evaluation; baseline and regular

  • Electrolytes, including calcium; baseline and as clinically indicated


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K - References

Abemaciclib drug monograph, Cancer Care Ontario.

Anastrozole drug monograph, Cancer Care Ontario.

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.

December 2019 Expanded to full regimen monograph


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M - Disclaimer

Regimen Abstracts
A Regimen Abstract is an abbreviated version of a Regimen Monograph and contains only top level information on usage, dosing, schedule, cycle length and special notes (if available). It is intended for healthcare providers and is to be used for informational purposes only. It is not intended to constitute or be a substitute for medical advice, and all uses of the Regimen Abstract are subject to clinical judgment. Such information is provided on an “as-is” basis, without any representation, warranty, or condition, whether express, or implied, statutory or otherwise, as to the information’s quality, accuracy, currency, completeness, or reliability, and Cancer Care Ontario disclaims all liability for the use of this information, and for any claims, actions, demands or suits that arise from such use.
Information in regimen abstracts is accurate to the extent of the ST-QBP regimen master listings, and has not undergone the full review process of a regimen monograph.  Full regimen monographs will be published for each ST-QBP regimen as they are developed.
Regimen Monographs
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
The information set out in the drug monographs, regimen monographs, appendices and symptom management information (for health professionals) contained in the Drug Formulary (the "Formulary") is intended for healthcare providers and is to be used for informational purposes only. The information is not intended to cover all possible uses, directions, precautions, drug interactions or adverse effects of a particular drug, nor should it be construed to indicate that use of a particular drug is safe, appropriate or effective for a given condition. The information in the Formulary is not intended to constitute or be a substitute for medical advice and should not be relied upon in any such regard. All uses of the Formulary are subject to clinical judgment and actual prescribing patterns may not follow the information provided in the Formulary.
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