palbociclib (Rx)

Adverse effects listed are for all grades of toxicity unless otherwise noted

>10% (Palbociclib with Letrozole)

WBC decreased (97%)

Neutrophils decreased (95%)

Neutropenia (80%)

Platelets decreased (63%)

Infections (60%)

Neutropenia, Grade 3 (56%)

Neutrophils decreased, Grade 3 (56%)

AST increased (52%)

ALT increased (43%)

Leukopenia (39%)

Fatigue (37%)

Nausea (35%)

WBC decreased, Grade 3 (35%)

Alopecia (33%)

Stomatitis (30%)

Diarrhea (26%)

Anemia (24%)

Leukopenia, Grade 3 (24%)

Rash (18%)

Asthenia (17%)

Vomiting (16%)

Thrombocytopenia (16%)

Dry skin (12%)

Pyrexia (12%)

>10% (Palbociclib with Fulvestrant)

WBC decreased (99%)

Neutrophils decreased (96%)

Neutropenia (83%)

Anemia (78%)

Platelets decreased (62%)

Neutrophils decreased, Grade 3 (56%)

Neutropenia, Grade 3 (55%)

Leukopenia (53%)

Infections (47%)

WBC decreased, Grade 3 (45%)

AST increased (43%)

Fatigue (41%)

ALT increased (36%)

Nausea (34%)

Leukopenia, Grade 3 (30%)

Anemia (30%)

Stomatitis (28%)

Diarrhea (24%)

Vomiting (19%)

Thrombocytopenia (23%)

Alopecia (18%)

Rash (17%)

Decreased appetite (16%)

Pyrexia (13%)

Neutropenia, Grade 4 (11%)

Neutrophils decreased, Grade 4 (11%)

1-10% (Palbociclib with Letrozole)

Neutropenia, Grade 4 (10%)

Anemia, Grade 3 (5%)

Infections, Grade 3 or 4 (1-6%)

AST increased, Grade 3 (3%)

ALT increased, Grade 3 (2%)

Thrombocytopenia, Grade 3 (1%)

Stomatitis, Grade 3 (1%)

Diarrhea, Grade 3 (1%)

Vomiting, Grade 3 (1%)

Leukopenia, Grade 4 (1%)

Rash, Grade 3 (1%)

WBC decreased, Grade 4 (1%)

Neutrophils decreased, Grade 4 (1%)

Platelets decreased, Grade 3 or 4 (1%)

1-10% (Palbociclib with Fulvestrant)

Asthenia (7.5%)

AST increased (7.5%)

Dysgeusia (6.7%)

Epistaxis (6.7%)

Lacrimation increased (6.4%)

Dry skin (6.1%)

ALT increased (5.8%)

Vision blurred (5.8%)

Anemia, Grade 3 (4%)

AST increased, Grade 3 (4%)

Dry eye (3.8%)

Infections, Grade 3 or 4 (1-3%)

Anemia, Grade 3 (3%)

Platelets decreased, Grade 3 (2%)

ALT increased, Grade 3 (2%)

Thrombocytopenia, Grade 3 (2%)

Fatigue, Grade 3 (2%)

Leukopenia, Grade 4 (1%)

Decreased appetite, Grade 3 (1%)

Vomiting, Grade 3 (1%)

Stomatitis, Grade 3 (1%)

Rash, Grade 3 (1%)

WBC decreased, Grade 4 (1%)

<1% (Palbociclib with Letrozole)

Anemia, Grade 4

Thrombocytopenia, Grade 4

Nausea, Grade 3

ALT increased, Grade 4

<1% (Palbociclib with Fulvestrant)

Pyrexia, Grade 3

Infections, Grade 4

Febrile neutropenia

Postmarketing Reports

Interstitial lung disease (ILD)/non-infectious pneumonitis

Contraindications

None

Cautions

Neutropenia observed in clinical trials; febrile neutropenia also reported; monitor CBC count prior to starting drug and at the beginning of each cycle, as well as on Day 14 of the first 2 cycles, and as clinically indicated; dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop grade 3 or 4 neutropenia

Grade 3 and 4 infections reported when administered in combination with an antiestrogen compared to patients receiving antiestrogen only; monitor and manage appropriately symptoms and signs of infection

Nausea, vomiting, diarrhea, and grade 1 or 2 stomatitis reported in clinical trials

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur; additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported; monitor for pulmonary symptoms indicative of ILD/pneumonitis which may include hypoxia, cough, and dyspnea; permanently discontinue therapy in patients with severe ILD or pneumonitis

Based on findings in animals and mechanism of action, palbociclib can cause fetal harm (see Pregnancy)

Drug interaction overview

• In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism of palbociclib
• Palbociclib is also a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans
• Avoid use with strong CYP3A inhibitors; if coadministration cannot be avoided, reduce the palbociclib dose (see Dosage Modifications)
• Avoid use with moderate or strong CYP3A inducers
• Palbociclib may increase sensitive CYP3A substrates with a narrow therapeutic index (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, midazolam, pimozide, quinidine, sirolimus, and tacrolimus)

Pregnancy

Based on findings in animals and mechanism of action, palbociclib can cause fetal harm when administered to a pregnant woman

In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose

Females of reproductive potential should have a pregnancy test before starting treatment

Based on findings in animals, male fertility may be compromised by treatment

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for at least 3 weeks after the last dose
• Male patients with female partners of reproductive potential: Because of potential for genotoxicity, use effective contraception during treatment and for 3 months after the last dose

Infertility

• Males: Based on animal studies, may impair fertility in males of reproductive potential

Lactation

Unknown if distributed in human breast milk; because many drugs are excreted in human milk

Owing to the potential for serious adverse reactions in breastfed infants, advise lactating women not to breastfeed while taking palbociclib and for at least 3 weeks after the last dose

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Cyclin dependent kinases (CDK) 4,6 inhibitor

Reduces cellular proliferation of ER-positive breast cancer cell lines by blocking progression of the cell from G1 into S phase of the cell cycle

Absorption

Bioavailability: 46%

Peak plasma time: 6-12 hr

Steady-state achieved: 8 days

Distribution

Protein bound: 85%

Vd: 2583 L

Metabolism

Extensively metabolized, primarily by CYP3A and SULT2A1

Elimination

Half-life: 29 hr (patients with advanced breast cancer)

Oral clearance: 63.1 L/hr

Excretion: 74.1% feces (2.3% unchanged); 17.5% urine (6.9% unchanged)

Majority of the dose eliminated in feces was metabolites

Oral Administration

Take with food

Swallow capsules whole; do not chew, crush, or open them prior to swallowing

Do not ingest capsule if it is broken, cracked, or otherwise not intact

Missed or vomited dose: An additional dose should NOT be taken that day; the next prescribed dose should be taken at the usual time

Storage

Store at 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)