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Chemotherapy and other systemic treatment regimens may change due to COVID-19. Find out more at Systemic Treatment Regimens During COVID-19.

A - Regimen Name

ABEMFLVS Regimen
Abemaciclib-Fulvestrant


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 hormone-receptor-positive, HER2-negative advanced breast cancer in patients whose disease had progressed while receiving endocrine therapy.


Supplementary Public Funding

fulvestrant
ODB - General Benefit (fulvestrant) (ODB Formulary )

 
B - Drug Regimen

Cycle 1:

abemaciclib
150 mg PO BID
(This drug is not currently publicly funded for this regimen and intent)
fulvestrant
500 mg IM Days 1 and 15

 

Cycle 2+:

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

Abemaciclib: Continuous treatment

Fulvestrant: REPEAT EVERY 28 DAYS

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 

Fulvestrant Action
Hematologic* Grade 3 Hold until ≤ grade 2; resume at same dose. Not applicable
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 Grade 1 (>ULN-3.0 x ULN)
Grade 2 (>3.0-5.0 x ULN)
WITHOUT increase in total bilirubin above 2 x ULN
No dose modification is required. Hold until recovery then restart
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 ↓. Discontinue
AST and/or ALT >3 times ULN with total bilirubin >2 times ULN (in the absence of cholestasis) Discontinue Discontinue
Grade 4 (ALT, AST >20 times ULN) Discontinue Discontinue
Hypersensitivity ≥ Grade 3 Hold until recovery to baseline or ≤ grade 1; resume at 1 dose level ↓. Consider discontinuing
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 Fulvestrant Dose
Mild or moderate impairment (Child-Pugh class A or B) No dosage adjustment necessary. Use with caution. No dose adjustment necessary.
Severe impairment (Child-Pugh class C) Reduce the abemaciclib frequency to once daily. Not studied. Use not recommended.

 


Renal Impairment

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

 


Dosage in the Elderly

No dosage adjustment is required.  Patients ≥65 years of age on abemaciclib 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.


 
F - Adverse Effects

Refer to abemaciclib, fulvestrant 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
  • Alopecia
  • Anorexia, weight loss
  • Creatinine increased
  • Headache
  • ↑ LFTs
  • Constipation
  • Cough, dyspnea
  • Rash, pruritus
  • Dizziness
  • Injection site reaction
  • Mucositis
  • Flu-like symptoms
  • Dry skin
  • Dysgeusia
  • Edema - limbs
  • Cardiotoxicity
  • Venous thromboembolism
  • Hypersensitivity
  • Nephrotoxicity
  • Pneumonitis
 
G - Interactions

Refer to abemaciclib, fulvestrant 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 abemaciclib is 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 abemaciclib is 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.

  • Fulvestrant may interfere with estradiol immunoassay measurements (falsely elevated estradiol levels) due to its structural similarity with estradiol.
 
H - Drug Administration and Special Precautions

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


Administration

Abemaciclib

  • Abemaciclib tablets should be swallowed whole (do not to 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.

  • Abemaciclib tablets contain lactose.  Use with caution in patients with lactose intolerance. 

  • 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).


Fulvestrant

  • Drug supplied by outpatient prescription

  • Intramuscular injection, slowly administered into the buttock (1-2 minutes per injection); caution due to proximity of the sciatic nerve and large blood vessels

  • According to local guidelines at the Cancer Centre or physician's office

  • Store refrigerated at 2 to 8°C in original package



Contraindications

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

  • Fulvestrant is also contraindicated in pregnant and breastfeeding women

 

Other Warnings/Precautions

  • There are no data regarding abemaciclib safety or efficacy in patients with prior exposure to other CDK 4/6 inhibitors.

  • Use fulvestrant with caution in patients with bleeding disorders or on anticoagulants

  • There is a potential osteoporosis risk due to fulvestrant's mechanism of action

 

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.  Fulvestrant is contraindicated in pregnancy. 

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

  • 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

    • Fulvestrant:  Probable

      • Observed in female animal studies.

 

 
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.

  • Creatinine; Baseline 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.

  • Clinical toxicity assessment for signs and symptoms of venous thrombosis, injection site reactions, infections, hot flashes, musculoskeletal, gastrointestinal, respiratory, dermatological effects and fatigue; At each visit
  • Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version

Suggested Clinical Monitoring

Electrolytes, including calcium; Baseline and as clinically indicated


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K - References

Abemaciclib drug monograph, Ontario Health (Cancer Care Ontario).

Fulvestrant drug monograph, Ontario Health (Cancer Care Ontario).

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.

September 2020 Changed fulvestrant to ODB general benefit


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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.
The format and content of the drug monographs, regimen monographs, appendices and symptom management information contained in the Formulary will change as they are reviewed and revised on a periodic basis. The date of last revision will be visible on each page of the monograph and regimen. Since standards of usage are constantly evolving, it is advised that the Formulary not be used as the sole source of information. It is strongly recommended that original references or product monograph be consulted prior to using a chemotherapy regimen for the first time.
Some Formulary documents, such as the medication information sheets, regimen information sheets and symptom management information (for patients), are intended for patients. Patients should always consult with their healthcare provider if they have questions regarding any information set out in the Formulary documents.
While care has been taken in the preparation of the information contained in the Formulary, 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.
CCO and the Formulary’s content providers shall have no liability, whether direct, indirect, consequential, contingent, special, or incidental, related to or arising from the information in the Formulary or its use thereof, whether based on breach of contract or tort (including negligence), and even if advised of the possibility thereof. Anyone using the information in the Formulary does so at his or her own risk, and by using such information, agrees to indemnify CCO and its content providers from any and all liability, loss, damages, costs and expenses (including legal fees and expenses) arising from such person’s use of the information in the Formulary.