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A - Regimen Name

FLVSPALB Regimen
Fulvestrant-palbociclib


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 the treatment of hormone-receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer in women whose disease has progressed on previous endocrine therapy.

Note: Pre- or perimenopausal women must also be treated with a luteinizing hormone releasing hormone (LHRH) agonist.

 
B - Drug Regimen

palbociclib
125 mg PO Days 1 to 21
(This drug is not currently publicly funded for this regimen and intent)

available in 75, 100 and 125 mg capsules

fulvestrant
500 mg IM Days 1, 15 and 29 (loading dose)
(This drug is not currently publicly funded for this regimen and intent)

 

THEN,

 

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

REPEAT EVERY 28 DAYS

Until disease progression or unacceptable toxicity

 
D - Premedication and Supportive Measures

Antiemetic Regimen:

Minimal – No routine prophylaxis; PRN recommended


Febrile Neutropenia Risk:

Low

Other Supportive Care:

Also refer to CCO Antiemetic Recommendations.

Pre and peri-menopausal women treated with palbociclib and fulvestrant should also be treated with luteinizing hormone releasing hormone (LHRH) agonists according to local clinical practice.

 
E - Dose Modifications

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

Dosage with toxicity

Dose levels:

Dose level Palbociclib Dose (mg/day) for 3 out of 4 weeks Fulvestrant (after loading dose in cycle 1)
0 125 500 mg IM q 4 weeks
-1 100 500 mg IM q 4 weeks
-2 75 500 mg IM q 4 weeks
-3 If further dose reduction required, discontinue 500 mg IM q 4 weeks

Do not retreat until ANC ≥ 1 x 109/L, platelets ≥ 50 x 109/L and non-hematologic toxicities have returned to baseline or Grade ≤ 1 (or at physician discretion, Grade ≤ 2, if not considered a patient safety risk). If conditions are not met, palbociclib should be delayed by 1 week, but fulvestrant may be continued. If no recovery after 2 weeks, discontinue palbociclib.

 

Palbociclib:

Toxicity

Grade

Palbociclib Dose

Hematologic

3

Day 1: Hold and repeat CBC within 1 week. When recovered to Grade ≤ 2, re-start next cycle at same dose.

Day 15 of 1st 2 cycles: Continue current dose to complete the cycle. Repeat CBC day 22.

If Grade 4 on Day 22, see Grade 4 recommendation below.

Consider dose reduction if > 1 week recovery or recurrent Grade 3 neutropenia in subsequent cycles.

 

3 with fever ≥ 38.5oC and/or infection

Hold until recovery to Grade ≤ 2. Restart at the next lower dose.

 

4

Hold until recovery to Grade ≤ 2. Restart at the next lower dose.

Non-hematologic

3 or 4 (if persisting despite medical treatment)

Hold until recovery to Grade ≤ 1 or Grade ≤ 2 (if not considered a safety risk). Restart at the next lower dose.

 

Fulvestrant:

Toxicity

Fulvestrant dose

Hypersensitivity

Consider discontinuing if severe.

Mild hepatotoxicity

Hold until recovery and then restart.

Moderate to severe hepatotoxicity

Discontinue.

 



Hepatic Impairment

Fulvestrant is metabolized primarily in the liver.  There are no efficacy and safety data in patients with breast cancer and hepatic impairment.

Mean fraction of unbound palbociclib in plasma increases with worsening hepatic function.

Hepatic Impairment

Palbociclib

Fulvestrant

Mild - Moderate (Child-Pugh class A and B)

No dosage adjustment needed.

Use with caution. No dosage adjustment needed.

Severe (Child-Pugh class C)

75 mg once daily (days 1 to 21; q28 days). Monitor for toxicity.

Not recommended.


Renal Impairment

CrCl (ml/min)

Palbociclib Fulvestrant
≥ 30 No dosage adjustment needed. No dosage adjustment needed.
< 30  No dosage adjustment needed. Use with caution; no data

 

Dosage based on Gender:

Gender and body weight had no significant effect on palbociclib exposure.


Dosage in the Elderly

No overall differences in efficacy were observed between patients aged 65 and older compared to younger patients. No dose adjustment needed for either palbociclib or fulvestrant. 

 

Dosage based on Ethnicity:

A pharmacology study in healthy volunteers indicated that bioavailability of palbociclib is higher (AUC 30%, Cmax 35%) in Japanese subjects compared to non-Asian subjects.  No dose modification is needed.

 


 
F - Adverse Effects

Refer to palbociclib, 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

  • Myelosuppression +/- infection, bleeding (may be severe)
  • Fatigue
  • Nausea, vomiting
  • Mucositis
  • Headache
  • Diarrhea
  • Constipation
  • Injection site reaction (may be severe)
  • Alopecia
  • Rash, dry skin
  • Anorexia
  • Cough, dyspnea
  • Insomnia
  • ↑ LFTs (may be severe)
  • Dizziness
  • Arterial thromboembolism
  • Venous thromboembolism
  • Hypersensitivity
 
G - Interactions

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


  • Palbociclib is a substrate and weak inhibitor of CYP3A and moderate substrate of P-gp.

  • Strong CYP3A inhibitors and inducers should be avoided during treatment.

  • If moderate CYP3A inhibitors cannot be avoided, no dose adjustment of palbociclib is needed.

  • Palbociclib should be given with food to reduce variable drug exposure and minimize drug interactions with drugs that alter gastric pH.

  • Consideration should be given to reducing the dose of CYP3A substrates with narrow therapeutic indices (e.g. cyclosporine).

  • 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 palbociclib, fulvestrant drug monograph(s) for additional details


Administration

Fulvestrant:

  • Drug supplied by outpatient prescription.

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

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

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

Palbociclib:

  • Palbociclib should be administered with food and taken at the same time each day.

  • Grapefruit, grapefruit juice and related products should be avoided (see Drug Interactions section).

  • Capsules should be swallowed whole and not chewed, crushed or opened prior to administration.

  • If a patient vomits or misses a dose, an extra dose should not be taken to make up for the missed dose. The next dose should be taken at the usual time.

  • Palbociclib should be stored at room temperature (20 to 25oC), with excursions permitted between 15 to 30oC.

 

Contraindications:

  • Patients who are hypersensitive to palbociclib, fulvestrant or any of their components.

  • In pregnant or breastfeeding women.

 

Other Warnings/Precautions:

  • As fatigue and dizziness have been reported with palbociclib, patients should exercise caution when driving or operating machinery.

  • Palbociclib contains lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

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

 

Pregnancy and Lactation:

  • Palbociclib and fulvestrant should not be used in pregnancy.  If treatment is used in women of childbearing potential, adequate contraception should be used by both sexes during treatment, and for at least 6 months after the last dose.
     

  • Fulvestrant is secreted into animal milk and is contraindicated in breastfeeding.
     

  • Breastfeeding is not recommended with palbociclib.
     

  • Animal data suggests that palbociclib may affect male fertility. Although not approved for use in men, sperm preservation should be considered prior to starting treatment in males. Male patients with female partners of reproductive potential should use effective contraception during treatment and at least 97 days after the last dose.

 

 
I - Recommended Clinical Monitoring

Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.

Recommended Clinical Monitoring

  • CBC; Baseline and before each cycle, on day 15 of the first 2 cycles, one week after Grade 3 neutropenia, and as clinically indicated. If Grade ≤ 2 neutropenia in the first 6 cycles, may monitor every 3rd cycle thereafter. 

  • Liver function tests; Baseline and as clinically indicated.

  • Renal function tests; Baseline and as clinically indicated.

  • Bone mineral density; Baseline and as clinically indicated.

  • Clinical toxicity assessment for injection site reactions, estrogen withdrawal symptoms, infection, bleeding, thromboembolism, rash, mucositis, fatigue, GI, musculoskeletal and neurologic effects; At each visit.

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

Suggested Clinical Monitoring

Renal function tests; Baseline and repeat as clinically indicated


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J - Administrative Information

Palbociclib:  Outpatient prescription for home administration

Fulvestrant:  Outpatient prescription; drug administration at Cancer Centre or physician's office


 
K - References

Fulvestrant and palbociclib drug monographs, Cancer Care Ontario.

Cristofanilli M, Turner NC, Bondarenko I, et al.  Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.  Lancet Oncol 2016;17(4):425-39.

Harbeck N, Iyer S, Turner N, et al.  Quality of life with palbociclib plus fulvestrant in previously treated hormone receptor-positive, HER2-negative metastatic breast cancer: patient-reported outcomes from the PALOMA-3 trial.  Ann Oncol 2016;27(6):1047-54.

June 2019 Updated emetic risk category


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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.