palbociclib 100 MG Oral Capsule

INDICATIONS AND USAGE IBRANCE is indicated for the treatment of adult patients with 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; or • fulvestrant in patients with disease progression following endocrine therapy. IBRANCE is indicated in combination with inavolisib and fulvestrant for the treatment of adult patients with endocrine-resistant, PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. IBRANCE is a kinase inhibitor indicated: • for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with: o an aromatase inhibitor as initial endocrine-based therapy ( 1 ); or o fulvestrant in patients with disease progression following endocrine therapy. ( 1 ) • in combination with inavolisib and fulvestrant for the treatment of adult patients with endocrine-resistant, PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy. ( 1 )

DOSAGE AND ADMINISTRATION IBRANCE tablets are taken orally with or without food in combination with an aromatase inhibitor, fulvestrant, or inavolisib and fulvestrant. ( 2 ) • Recommended starting dose: 125 mg once daily taken with or without food for 21 days followed by 7 days off treatment. ( 2.1 ) • Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability. ( 2.2 ) 2.1 Recommended Dose and Schedule The recommended dose of IBRANCE is a 125 mg tablet taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE tablet may be taken with or without food [see Clinical Pharmacology (12.3) ] . Administer the recommended dose of an aromatase inhibitor when given with IBRANCE. Please refer to the Full Prescribing Information for the aromatase inhibitor being used. When given with IBRANCE, the recommended dose of fulvestrant is 500 mg administered on Days 1, 15, 29, and once monthly thereafter. Please refer to the Full Prescribing Information of fulvestrant. Refer to the Full Prescribing Information for inavolisib and fulvestrant for dosing information . Advise patients to take their dose of IBRANCE at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. IBRANCE tablets should be swallowed whole (do not chew, crush, or split them prior to swallowing). Tablets should not be ingested if they are broken, cracked, or otherwise not intact. Pre/perimenopausal women treated with the combination IBRANCE plus an aromatase inhibitor or fulvestrant therapy or IBRANCE plus inavolisib and fulvestrant should also be treated with luteinizing hormone-releasing hormone (LHRH) agonists according to current clinical practice standards. For men treated with combination IBRANCE plus aromatase inhibitor or IBRANCE plus inavolisib and fulvestrant therapy, consider treatment with an LHRH agonist according to current clinical practice standards. 2.2 Dose Modification The recommended dose modifications for adverse reactions are listed in Tables 1, 2, and 3. Table 1. Recommended Dose Modification for Adverse Reactions Dose Level Dose 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. Table 2. Dose Modification and Management – Hematologic Toxicities Table applies to all hematologic adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections). Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events; LLN=lower limit of normal. Monitor complete blood counts prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, monitor complete blood counts for subsequent cycles every 3 months, prior to the beginning of a cycle and as clinically indicated. CTCAE Grade Dose Modifications Grade 1 or 2 No dose adjustment is required. Grade 3 Day 1 of cycle : Withhold IBRANCE, repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose . Day 15 of first 2 cycles : If Grade 3 on Day 15, continue IBRANCE at current dose to complete cycle and repeat complete blood count on Day 22. If Grade 4 on Day 22, see Grade 4 dose modification guidelines below. Consider dose reduction in cases of prolonged (>1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles. Grade 3 neutropenia Absolute neutrophil count (ANC): Grade 1: ANC < LLN – 1500/mm 3 ; Grade 2: ANC 1000 – <1500/mm 3 ; Grade 3: ANC 500 – <1000/mm 3 ; Grade 4: ANC <500/mm 3 . with fever ≥38.5 °C and/or infection At any time : Withhold IBRANCE until recovery to Grade ≤2. Resume at the next lower dose . Grade 4 At any time : Withhold IBRANCE until recovery to Grade ≤2. Resume at the next lower dose . Table 3. Dose Modification and Management – Non-Hematologic Toxicities CTCAE Grade Dose Modifications Grading according to CTCAE 4.0. CTCAE=Common Terminology Criteria for Adverse Events. Grade 1 or 2 No dose adjustment is required. Grade ≥3 non-hematologic toxicity (if persisting despite optimal medical treatment) Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose . Permanently discontinue IBRANCE in patients with severe interstitial lung disease (ILD)/pneumonitis. Refer to the Full Prescribing Information for coadministered endocrine therapy and/or inavolisib dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications. Dose Modifications for Use With Strong CYP3A Inhibitors Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ]. Dose Modifications for Hepatic Impairment No dose adjustment is required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

WARNINGS AND PRECAUTIONS • Neutropenia: Monitor complete blood count prior to start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated. ( 2.2 , 5.1 ) • Interstitial Lung Disease (ILD)/Pneumonitis: Severe and fatal cases of ILD/pneumonitis have been reported. Monitor for pulmonary symptoms of ILD/pneumonitis. Interrupt IBRANCE immediately in patients with suspected ILD/pneumonitis. Permanently discontinue IBRANCE if severe ILD/pneumonitis occurs. ( 5.2 ) • Embryo-Fetal Toxicity: IBRANCE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Neutropenia Neutropenia was the most frequently reported adverse reaction in PALOMA-2 with an incidence of 80% and PALOMA-3 with an incidence of 83%. A Grade ≥3 decrease in neutrophil counts was reported in 66% of patients receiving IBRANCE plus letrozole in PALOMA-2 and 66% of patients receiving IBRANCE plus fulvestrant in PALOMA-3. In PALOMA-2 and PALOMA-3, the median time to first episode of any grade neutropenia was 15 days and the median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions (6.1) ] . Monitor complete blood counts prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 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 [see Dosage and Administration (2.2) ] . Febrile neutropenia has been reported in 1.8% of patients exposed to IBRANCE across PALOMA-2 and PALOMA-3. One death due to neutropenic sepsis was observed in PALOMA-3. Physicians should inform patients to promptly report any episodes of fever [see Patient Counseling Information (17) ] . 5.2 Interstitial Lung Disease (ILD)/Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD) and/or pneumonitis can occur in patients treated with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1% of IBRANCE-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 [see Adverse Reactions (6.2) ] . Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnea). In patients who have new or worsening respiratory symptoms and are suspected to have developed pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis [see Dosage and Administration (2.2) ] . 5.3 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of palbociclib to pregnant rats and rabbits during organogenesis resulted in embryo-fetal toxicity at maternal exposures that were ≥4 times the human clinical exposure based on area under the curve (AUC). Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose [see Use in Specific Populations (8.1 and 8.3) and Clinical Pharmacology (12.1) ] .

CONTRAINDICATIONS None. None. ( 4 )

Mechanism of Action Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of signaling pathways which lead to cellular proliferation. In vitro, 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. In vitro 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. Human bone marrow mononuclear cells treated with palbociclib in the presence or absence of an anti-estrogen in vitro did not become senescent and resumed proliferation following palbociclib withdrawal.