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palbociclib

( PAL boe SYE klib )
Funding:
Exceptional Access Program
  • palbociclib - For the treatment of patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER 2)-negative, unresectable locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant, according to clinical criteria
Other Name(s): Ibrance™
Appearance: Tablet or capsule in various strengths and colours
A - Drug Name

palbociclib

COMMON TRADE NAME(S):   Ibrance™

 
B - Mechanism of Action and Pharmacokinetics

Palbociclib is a selective, reversible small molecule inhibitor of cyclin-dependent kinases (CDK) 4 and 6. The drug inhibits cyclin D-CDK 4/6 complex activity, blocking cell cycle progression from G1 to S phase. Palbociclib in combination with an anti-estrogen agent inhibits cell proliferation and induction of cell senescence in estrogen receptor (ER) positive breast cancer models.



Absorption
Bioavailability

46% (mean)

Peak plasma levels

6 to 12 hours (capsule); 4 to 12 hours (tablet)

Time to reach steady state

8 days

Effects with food

Capsule: When administered with food, AUC and Cmax increased (up to 21% and 38%, respectively) and exposure variability decreased. Palbociclib capsules should be taken with food.

Tablet: When administered with food, AUC and Cmax increased up to 22% and 26%, respectively; food had no significant impact on exposure variability. Palbociclib tablets may be taken with or without food.


Distribution
PPB

85%

Metabolism

Palbociclib undergoes hepatic metabolism via oxidation and sulfonation, primarily by CYP3A and sulfotransferase (SULT2A1) enzymes; acylation and glucuronidation are minor metabolic pathways.

Inactive metabolites

Yes

Elimination
Half-life

29 hours (mean plasma)

Feces

74%

Urine

18%

 
C - Indications and Status
Health Canada Approvals:

  • Breast cancer

(Includes conditional approvals)
Refer to the product monograph for a full list and details of approved indications.



 
D - Adverse Effects

Emetogenic Potential:  

Minimal – No routine prophylaxis; PRN recommended

The following adverse effects occurred in patients with breast cancer treated with palbociclib plus fulvestrant in a Phase III study, where the incidence was at least 2% greater than the placebo plus fulvestrant arm. The table also includes severe or life-threatening adverse effects from other sources or post-marketing.

ORGAN SITE SIDE EFFECT* (%) ONSET**
Cardiovascular Venous thromboembolism (1%) (pulmonary embolism) E
Dermatological Alopecia (15%) E
Rash, pruritus (14%) E
Gastrointestinal Anorexia (13%) E
Constipation (17%) E
Diarrhea (19%) E
Mucositis (25%) E
Nausea, vomiting (29%) E
General Edema - limbs (8%) E
Fatigue (38%) E
Hematological Myelosuppression ± infection, bleeding (79%) (62% severe) E
Nervous System Dizziness (11%) E
Dysgeusia (6%) E
Headache (21%) E
Insomnia (11%) E
Respiratory Cough, dyspnea (13%) E
Pneumonitis (1%) E


* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare" may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal reports.

** I = immediate (onset in hours to days)     E = early (days to weeks)
D = delayed (weeks to months)      L = late (months to years)

The most common side effects for palbociclib include myelosuppression ± infection, bleeding, fatigue, nausea, vomiting, mucositis, headache, diarrhea, constipation, alopecia, rash, pruritus and anorexia.

Neutropenia was the most frequently reported adverse effect with a median onset of 15 days. Febrile neutropenia, including one fatal case, has been was reported in 2% of patients across clinical trials.

Infections were reported more frequently. Patients should be warned of the increased risk of infection and promptly report any occurrences of fever to their health care team.

Severe or life-threatening interstitial lung disease/pneumonitis has been reported in combination with endocrine therapy in clinical trials and post-marketing (including fatal cases).

 
E - Dosing

Refer to protocol by which patient is being treated.

Pre- and perimenopausal women treated with palbociclib and an aromatase inhibitor or fulvestrant should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to local clinical practice.



Adults:

Oral: 125 mg Daily on Days 1 to 21, every 28 days

in combination with an aromatase inhibitor (e.g., letrozole) or fulvestrant. Refer to regimen monographs for dosing details.


Dosage with Toxicity:

Dose Level

Palbociclib Dose (mg/day) for 3 out of 4 weeks

0 125
-1 100
-2 75
-3 If further dose reduction required, discontinue.


 

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.

Symptoms of interstitial lung disease (ILD)/pneumonitis (treatment–related)

Any Hold dose and investigate; discontinue if severe ILD confirmed.
Other 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.


Dosage with Hepatic Impairment:

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

Hepatic Impairment Starting Dose
Mild - Moderate (Child-Pugh class A and B) No dosage adjustment needed.
Severe (Child-Pugh class C) 75 mg once daily (days 1 to 21; q28 days). Monitor for toxicity.


Dosage with Renal Impairment:

No adjustment is required for CrCl > 15 mL/min. There is no data available in patients requiring hemodialysis.



Dosage in the elderly:

No overall differences in efficacy were observed between patients aged 65 and older compared to younger patients. When combined with letrozole, patients ≥ 65 were more likely to experience anemia.



Dosage based on gender:

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



Dosage based on ethnicity:

No dose modification is required based on pharmacokinetic, safety and efficacy data across Asian and non-Asian populations.



Children:

The safety and efficacy of palbociclib has not been studied in children under 18 years.



 
F - Administration Guidelines

  • Palbociclib capsules should be administered with food; palbociclib tablets may be given with or without food.
  • Capsules or tablets should be swallowed whole and not chewed, crushed, opened, or split prior to administration.
  • If a patient vomits or misses a dose, an extra dose should not be taken to make up for the vomited or missed dose. The next dose should be taken at the usual time.
  • Grapefruit, pomegranate, starfruit, Seville oranges, their juices or products should be avoided during palbociclib treatment.
  • Capsules should be stored at 20 to 25oC, with excursions permitted between 15 to 30oC. Tablets should be stored at 15 to 30oC in original packaging to protect from moisture.


 
G - Special Precautions
Contraindications:

  • Patients who are hypersensitive to palbociclib or any ingredient in the formulation or component in the container.
     

Other Warnings/Precautions:

  • As fatigue and dizziness have been reported, patients should exercise caution when driving or operating machinery.
  • Capsules contain lactose; carefully consider use in patients with hereditary galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.


Other Drug Properties:

  • Carcinogenicity: Unknown

    An increased incidence of microglial cell tumors was observed male rats; the relevance to humans is unknown.

     

Pregnancy and Lactation:
  • Genotoxicity: Probable
  • Mutagenicity: No
  • Fetotoxicity: Yes

    Palbociclib is not recommended for use in pregnancy. Adequate contraception should be used by both sexes during treatment, and for at least 21 days after the last dose (for females) and 97 days after the last dose (for males).

  • Excretion into breast milk: Unknown

    Breastfeeding is not recommended.

  • Fertility effects: Probable

    Animal data suggest that palbociclib may affect male fertility. Sperm preservation should be considered prior to starting treatment in males. 

 
H - Interactions

Palbociclib is a substrate and weak inhibitor of CYP3A and a moderate substrate of P-gp. Drug interactions are possible with strong CYP3A inducers and inhibitors. Palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C9 and 2D6 and not an inducer of CYP1A2, 2B6, 2C8 and 3A4 in vitro.

The drug has a low potential to inhibit drug transporters P-gp, BCRP, OAT1, OAT3, OCT2, OATP1B1 and OATP1B3. Palbociclib is not a substrate of OATP1B1 and OATP1B3 (in vitro studies).

There are no drug interactions with letrozole or goserelin.

Palbociclib solubility is pH dependent. Drug interactions with proton pump inhibitors are minimized when palbociclib capsules are given with food; food also reduces drug exposure variability of palbociclib capsules.

AGENT EFFECT MECHANISM MANAGEMENT
CYP3A inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) ↑ palbociclib concentration and/or toxicity ↓ metabolism of palbociclib Avoid strong CYP3A inhibitors.
Strong and moderate CYP3A inducers (i.e. phenytoin, rifampin, dexamethasone, carbamazepine, phenobarbital, St. John’s Wort, etc) ↓ palbociclib concentration and/or efficacy ↑ metabolism of palbociclib Avoid CYP3A inducers. If use of moderate inducer cannot be avoided, no dose adjustment to palbociclib is needed.
Antacids and PPIs (e.g. rabeprazole) ↓ palbociclib exposure when PPI and palbociclib capsules given in fasted conditions; minimal effect when palbociclib capsules given with food Palbociclib has pH-dependent solubility; reduced palbociclib capsule solubility with increasing pH. To minimize interaction with antacids and PPIs, palbociclib capsules should be given with food.
CYP3A substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines, dihydropyridine calcium-channel blockers, certain HMG-CoA reductase inhibitors) ↑ substrate concentration and/or toxicity Palbociclib is a weak inhibitor of CYP3A. Consider reducing the dose of CYP3A substrates with narrow therapeutic indices (e.g. cyclosporine)
 
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

Monitor Type Monitor Frequency

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 neutropenia Grade 2 or less 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

Clinical toxicity assessment for infection, bleeding, thromboembolism, pneumonitis, rash, headache, mucositis, fatigue and GI effects

At each visit

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



 
J - Supplementary Public Funding

Exceptional Access Program (EAP Website)

  • palbociclib - For the treatment of patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER 2)-negative, unresectable locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant, according to clinical criteria

 
K - References

Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35.

Product Monograph: Ibrance (palbociclib). Pfizer Canada Inc. January 24, 2020.


April 2021 Updated indication and dosing description

 
L - Disclaimer

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.

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