Indications

Palcigen 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:

• An aromatase inhibitor as initial endocrine-based therapy in postmenopausal women; or
• Fulvestrant in women with disease progression following endocrine therapy.

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Pharmacology

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.

Dosage & Administration

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:

• Recommended Starting Dose: 125 mg/day
• First Dose Reduction: 100 mg/day
• Second Dose Reduction: 75 mg/day

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.

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Interaction

Palcigen is primarily metabolized by CYP3A and Sulfotransferase (SULT) enzyme SULT2A1. Palcigen is a
time-dependent inhibitor of CYP3A.

Agents That May Increase Palcigen Plasma Concentrations: Effect of CYP3A-Inhibitors: Coadministration of a strong CYP3A inhibitor (Itraconazole) increased the plasma exposure of Palcigen 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 Palcigen treatment. If coadministration of Palcigen with a strong CYP3A inhibitor cannot be avoided, reduce the dose of Palcigen.

Agents That May Decrease Palcigen Plasma Concentrations: Effect of CYP3A Inducers: Coadministration of a strong CYP3A Inducer (Rifampin) decreased the plasma exposure of Palcigen 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 Palcigen: Coadministration of Midazolam with multiple doses of Palcigen 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 Palcigen may increase its exposure.

Side Effects

Common side effects of Palcigen include: WBC decreased, Neutrophils decreased, Neutropenia, Platelets decreased, infections, AST increased, ALT increased, Leukopenia, Fatigue, Nausea, Hair loss, Inflammation of the mouth and lips, Diarrhea, Anemia, Rash, Weakness/lethargy, Vomiting, Thrombocytopenia, Dry skin, Fever.

Pregnancy & Lactation

Palbociclib can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.

Precautions & Warnings

Neutropenia: Neutropenia was the most frequently reported adverse reaction in Study 1 (PALOMA-2) with an incidence of 80% and Study 2 (PALOMA-3) with an incidence of 83%. A Grade 3 in neutrophil counts was reported in 66% of patients receiving Palcigen plus letrozole in Study 1 and 66% of patients receiving Palcigen plus fulvestrant in Study In Study 1 and 2, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade 3 was 7 days. Monitor complete blood counts prior to Palcigen therapy and at the beginning of each cycle, well as on Day 15 of the 2 cycles, and as clinically dose. Dose or delay in treatment cycles recommended for patients who develop Grade 3 or 4 neutropenia. Febrile neutropenia has been reported in 1.8% of patients exposed to Palcigen Studies 1 and 2. One death due to neutropenia was observed in Study Physicians should inform patients to promptly report any of fever.

Interstitial Lung Disease (ILD)/Pneumonitis: Severe, life-threatening, fatal interstitial lung disease (ILD) and/or pneumonitis can occur in treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including Palcigen when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of Palcigen treated patients had ILD/pneumonitis of any grade, 0.1 % had Grade 3 or 4 and no fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the postmarketing setting, with fatalities reported. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis hypoxia, cough, In patients who have new or symptoms and suspected to have developed interrupt Palcigen immediately and evaluate the Permanently discontinue Palcigen in patients with severe ILD or pneumonitis.

Embryo Fetal Toxicity: Based on findings from animal studies and its mechanism of action, Palcigen can cause fetal harm when administered to a pregnant woman. In animal reproduction studies administration of Palcigen to pregnant and during resulted in embryo-fetal toxicity at maternal that were 4 times the human clinical exposure based on area under the (AUC). Advise pregnant women of the potential risk to a Advise females of reproductive potential to use effective contraception during treatment with Palcigen and for at least 3 weeks after the last dose.

Overdose Effects

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

Therapeutic Class

Protein kinase inhibitor

Storage Conditions

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