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palbociclib
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.
| 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. |
| PPB |
85% |
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 |
| Half-life |
29 hours (mean plasma) |
| Feces |
74% |
| Urine |
18% |
- Breast cancer
(Includes conditional approvals)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
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).
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.
in combination with an aromatase inhibitor (e.g., letrozole) or fulvestrant. Refer to regimen monographs for dosing details.
| 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. |
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. |
No adjustment is required for CrCl > 15 mL/min. There is no data available in patients requiring hemodialysis.
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.
Gender and body weight had no significant effect on drug exposure.
No dose modification is required based on pharmacokinetic, safety and efficacy data across Asian and non-Asian populations.
The safety and efficacy of palbociclib has not been studied in children under 18 years.
- 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.
- Patients who are hypersensitive to palbociclib or any ingredient in the formulation or component in the container.
- 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.
-
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.
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) |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| 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
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
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
Refer to the New Drug Funding Program or Ontario Public Drug Programs websites for the most up-to-date public funding information.
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