Palbociclib is a kinase inhibitor indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:
Palbociclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are key regulators of cell cycle progression and act downstream of growth signaling pathways that control cell proliferation. It inhibits proliferation of estrogen receptor (ER)-positive breast cancer cells by preventing transition from the G1 phase to the S phase of the cell cycle. When combined with antiestrogens, Palbociclib decreases retinoblastoma (RB) protein phosphorylation, resulting in reduced E2F signaling and stronger cell cycle arrest compared to either agent alone. This combination also enhances cellular senescence, which may persist for several days after drug withdrawal and is further increased when antiestrogen therapy is continued. Preclinical studies in ER-positive breast cancer models show that Palbociclib with letrozole provides greater inhibition of RB phosphorylation, downstream signaling, and tumor growth than monotherapy.
The recommended dose of Palbociclib is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. Palbociclib should be taken with food. Patients should be encouraged to take their dose of Palbociclib at approximately the same time each day. For men treated with combination Palbociclib plus aromatase inhibitor therapy, consider treatment with an LHRH agonist according to current clinical practice standards.
Recommended Dose Modification for Adverse Reactions:
If further dose reduction below 75 mg/day is required, discontinue. Or, as directed by the registered physician.
Use in Children: Palbociclib is not indicated for use in children.
Palbociclib is primarily metabolized by CYP3A and the sulfotransferase (SULT) enzyme SULT2A1. It is also a time-dependent inhibitor of CYP3A.
Agents That May Increase Palbociclib Plasma Concentrations: Effect of CYP3A Inhibitors: Coadministration with a strong CYP3A inhibitor (Itraconazole) increased Palbociclib exposure by 87% in patients. Concomitant use of strong CYP3A inhibitors such as Clarithromycin, Indinavir, Itraconazole, Ketoconazole, Lopinavir/Ritonavir, Nefazodone, Nelfinavir, Posaconazole, Ritonavir, Saquinavir, Telaprevir, Telithromycin, and Voriconazole should be avoided. Grapefruit or grapefruit juice should also be avoided during Palbociclib treatment. If coadministration with a strong CYP3A inhibitor cannot be avoided, the dose of Palbociclib should be reduced.
Agents That May Decrease Palbociclib Plasma Concentrations: Effect of CYP3A Inducers: Coadministration with a strong CYP3A inducer (Rifampin) decreased Palbociclib exposure by 85% in healthy subjects. Concomitant use of strong CYP3A inducers such as Phenytoin, Rifampin, Carbamazepine, Enzalutamide, and St. John’s Wort should be avoided.
Drugs That May Have Their Plasma Concentrations Altered by Palbociclib: Coadministration of Midazolam with multiple doses of Palbociclib increased Midazolam exposure by 61% compared to Midazolam alone. Dose reduction may be required for sensitive CYP3A substrates with a narrow therapeutic index (e.g., Alfentanil, Cyclosporine, Dihydroergotamine, Ergotamine, Everolimus, Fentanyl, Pimozide, Quinidine, Sirolimus, and Tacrolimus), as Palbociclib may increase their exposure.
Common adverse effects of Palbociclib include decreased white blood cells (WBC), decreased neutrophils, neutropenia, decreased platelets, infections, increased AST and ALT, leukopenia, fatigue, nausea, hair loss, inflammation of the mouth and lips, diarrhea, anemia, rash, weakness/lethargy, vomiting, thrombocytopenia, dry skin, and fever.
Palbociclib may cause fetal harm when administered to a pregnant woman. Pregnant women should be informed of the potential risk to the fetus. The estimated risk of major birth defects in clinically recognized pregnancies is 2%–4%, and miscarriage is 15%–20%.
Neutropenia: Neutropenia is the most common adverse reaction, reported in Study 1 (PALOMA-2) with an incidence of 80% and in Study 2 (PALOMA-3) with 83%. Grade 3 neutropenia occurred in 66% of patients receiving Palbociclib plus letrozole in Study 1 and 66% of patients receiving Palbociclib plus fulvestrant in Study 2. In both studies, the median time to first episode of any-grade neutropenia was 15 days, and the median duration of Grade 3 neutropenia was 7 days. Complete blood counts should be monitored before starting Palbociclib, at the beginning of each treatment cycle, on Day 15 of the first 2 cycles, and as clinically indicated. Dose interruption or delay is recommended for patients who develop Grade 3 or 4 neutropenia. Febrile neutropenia was reported in 1.8% of patients in Studies 1 and 2. One death due to neutropenia was observed. Patients should be advised to report any fever immediately.
Interstitial Lung Disease (ILD)/Pneumonitis: Serious, life-threatening, and fatal ILD and/or pneumonitis may occur in patients treated with CDK4/6 inhibitors, including Palbociclib, when used with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of patients developed ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4 events, and no fatal cases were reported in trials; however, postmarketing fatalities have been observed. Patients should be monitored for respiratory symptoms such as hypoxia, cough, or dyspnea. If ILD/pneumonitis is suspected, Palbociclib should be interrupted and the patient evaluated. Permanent discontinuation is recommended in severe cases.
Embryo-Fetal Toxicity: Based on animal studies and its mechanism of action, Palbociclib can cause fetal harm when administered during pregnancy. In animal studies, administration during organogenesis resulted in embryo-fetal toxicity at exposures approximately 4 times the human clinical exposure (AUC). Pregnant women should be informed of the potential risk to the fetus. Females of reproductive potential should use effective contraception during treatment and for at least 3 weeks after the final dose.
There is no known specific antidote for Palbociclib. Management of overdose should consist of general supportive care and symptomatic treatment.
Protein kinase inhibitor
Store below 30°C, protected from light and moisture. Keep out of the reach of children.
What is Palbociclib for?
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Can Palbociclib be taken during pregnancy?
