Palbociclib

Palbociclib is indicated for the treatment of HR-positive, HER2-negative advanced or metastatic breast cancer in combination with: an aromatase inhibitor as initial endocrine based therapy in postmenopausal women; or. fulvestrant in women with disease progression following endocrine therapy.

Selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6.

Palbociclib is an inhibitor of Cyclin-dependent kinases (CDK) 4 and 6. cyclin D1 and CDK4/6 are downstream of signaling pathways that lead to cellular proliferation. Palbociclib reduced cellular proliferation of Estrogen receptor (ER)-positive breast cancer cell lines by blocking progression of the cell from G1 into s phase of the cell cycle. Treatment of breast cancer cell lines with the combination of Palbociclib and antiestrogens leads to decreased retinoblastoma (RB) protein phosphorylation resulting in reduced E2F expression and signaling, and increased growth arrest compared to treatment with each drug alone. Treatment of ER-positive breast cancer cell lines with the combination of Palbociclib and antiestrogens led to increased cell senescence compared to each drug alone, which was sustained for up to 6 days following Palbociclib removal and was greater if antiestrogen treatment was continued. In vivo studies using a patient-derived ER-positive breast cancer xenograft model demonstrated that the combination of Palbociclib and letrozole increased the inhibition of RB phosphorylation, downstream signaling, and tumor growth compared to each drug alone.

Breast Cancer Indicated for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer in combination with an aromatase inhibitor as initial endocrine based therapy in postmenopausal women, or with fulvestrant in women with disease progression following endocrine therapy Starting dose: 125 mg PO qDay with food x21 days followed by 7 days off therapy to comprise a complete cycle of 28 days Initial endocrine-based therapy in combination with an aromatase inhibitor: Refer to aromatase inhibitor (eg, letrozole, anastrozole, exemestane) prescribing information for dose Disease progression following endocrine therapy: When given with palbociclib, the fulvestrant dose is 500 mg IM on days 1, 15, 29, and once monthly thereafter

Palbociclib is primarily metabolized by CYP3A and Sulfotransferase (SULT) enzyme SULT2A1. Palbociclib is a time-dependent inhibitor of CYP3A. Agents That May Increase Palbociclib Plasma Concentrations: Effect of CYP3A-Inhibitors: Coadministration of a strong CYP3A inhibitor (Itraconazole) increased the plasma exposure of Palbociclib in patients by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., Clarithromycin, Indinavir, Itraconazole, Ketoconazole, Lopinavir/Ritonavir, Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Saquinavir, Telaprevir, Telithromycin, And Voriconazole). Avoid grapefruit or grapefruit juice during Palbociclib treatment. If coadministration of Palbociclib with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Palbociclib. Agents That May Decrease Palbociclib Plasma Concentrations: Effect of CYP3A Inducers: Coadministration of a strong CYP3A Inducer (Rifampin) decreased the plasma exposure of Palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (E.G., Phenytoin, Rifampin, Carbamazepine, Enzalutamide, and St John’s Wort). Drugs That May Have Their Plasma Concentrations Altered By Palbociclib: Coadministration of Midazolam with multiple doses of Palbociclib increased the Midazolam plasma exposure by 61%, in patients, compared to administration of Midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., Alfentanil, Cyclosporine, Dihydroergotamine, Ergotamine, Everolimus, Fentanyl, Pimozide, Quinidine, Sirolimus, And Tacrolimus) may need to be reduced, as Palbociclib may increase its exposure.

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 Based on findings in animals and mechanism of action, palbociclib can cause fetal harm.

Neutropenia, all grades (75%) Neutropenia, grade 3 (48%) Leukopenia, all grades (43%) Fatigue, all grades (41%) Anemia, all grades (35%) Upper respiratory tract infection, all grades (31%) Stomatitis, all grades (25%) Nausea, all grades (25%) Alopecia, grade 1 (22%) Diarrhea, all grades (21%) Leukopenia, grade 3 (19%) Thrombocytopenia, all grades (17%) Decreased appetite, all grades (16%) Vomiting, all grades (15%) Peripheral neuropathy, all grades (13%) Asthenia, all grades (13%) Epistaxis, all grades (11%) 1-10% Neutropenia, grade 4 (6%) Anemia, grade 3 (5%) Diarrhea, grade 3 (4%) Thrombocytopenia, grade 3 (2%) Nausea, grade 3 (2%) Fatigue, grades 3/4 (2%) Asthenia, grade 3 (2%) Upper respiratory treact infection, grade 3 (1%) Decreased appetite, grade 3 (1%)

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 Advise females of reproductive potential to use effective contraception during treatment and for at least 2 weeks after the last dose; advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment Lactation Unknown if distributed in human breast milk; because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from palbociclib, advise a nursing woman to discontinue breastfeeding during treatment

There is no known antidote for Palbociclib. The treatment of overdose of Palbociclib should consist of general supportive measures.

Keep below 30°C temperature, away from light & moisture. Keep out of the reach of children.

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