IBRANCE

capsules for oral administration contain 125 mg, 100 mg, or 75 mg of palbociclib, a kinase inhibitor.

The molecular formula for palbociclib is

C 24 H 29 N 7 O 2.

The molecular weight is 447.54 daltons.

The chemical name is 6-acetyl-8-cyclopentyl-5-methyl-2-{[5-(piperazin-1-yl)pyridin-2-yl]amino}pyrido[2,3 - d ]pyrimidin-7(8 H )-one, and its structural formula is: Palbociclib is a yellow to orange powder with pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen).

At or below pH 4, palbociclib behaves as a high-solubility compound.

Above pH 4, the solubility of the drug substance reduces significantly.

Inactive ingredients

Microcrystalline cellulose, lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium stearate, and hard gelatin capsule shells.

The light orange, light orange/caramel, and caramel opaque capsule shells contain gelatin, red iron oxide, yellow iron oxide, and titanium dioxide; the printing ink contains shellac, titanium dioxide, ammonium hydroxide, propylene glycol, and simethicone.

• 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.

• 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; or o fulvestrant in patients with disease progression following endocrine therapy.

• 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.

Palbociclib is an inhibitor of cyclin-dependent kinases (CDK) 4 and 6.

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. 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer.

Palbociclib had no large effect on

QTc (i.e., >20 ms) at 125 mg once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. 12.3 Pharmacokinetics The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects.

The mean maximum observed concentration (C max ) of palbociclib is generally observed between to 12 hours (time to reach maximum concentration, T max ) following oral administration.

The mean absolute bioavailability of

IBRANCE after an oral 125 mg dose is 46%.

In the dosing range of 25 mg to 225 mg, the AUC and C max increased proportionally with dose in general.

Steady state was achieved within 8 days following repeated once daily dosing.

With repeated once daily administration, palbociclib accumulated with a median accumulation ratio of 2.4 (range 1.5 to 4.2).

Food effect

Palbociclib absorption and exposure were very low in approximately 13% of the population under the fasted condition.

Food intake increased the palbociclib exposure in this small subset of the population, but did not alter palbociclib exposure in the rest of the population to a clinically relevant extent.

Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of IBRANCE with food.

Compared to

IBRANCE given under overnight fasted conditions, the population average area under the concentration-time curve from zero to infinity (AUC INF ) and C max of palbociclib increased by 21% and 38%, respectively, when given with high-fat, high-calorie food (approximately to 1000 calories with 150, 250, and to 600 calories from protein, carbohydrate, and fat, respectively), by 12% and 27%, respectively, when given with low-fat, low-calorie food (approximately to 500 calories with 120, 250, and to 35 calories from protein, carbohydrate, and fat, respectively), and by 13% and 24%, respectively, when moderate-fat, standard calorie food (approximately to 700 calories with to 105, 250 to and 175 to 245 calories from protein, carbohydrate, and fat, respectively) was given 1 hour before and 2 hours after IBRANCE dosing.

Binding of palbociclib to human plasma proteins in vitro was approximately 85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL.

The mean fraction unbound (f u ) of palbociclib in human plasma in vivo increased incrementally with worsening hepatic function.

There was no obvious trend in the mean palbociclib f u in human plasma in vivo with worsening renal function.

The geometric mean apparent volume of distribution (V z /F) was 2583 L with a coefficient of variation (CV) of 26%.

In vitro and in vivo studies indicated that palbociclib undergoes hepatic metabolism in humans.

Following oral administration of a single 125 mg dose of [ 14 C]palbociclib to humans, the primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways.

Palbociclib was the major circulating drug-derived entity in plasma (23%).

The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta.

Palbociclib was extensively metabolized with unchanged drug accounting for 2.3% and 6.9% of radioactivity in feces and urine, respectively.

In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 26% of the administered dose.

In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant SULT enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.

The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.1 L/hr (29% CV), and the mean (± standard deviation) plasma elimination half-life was 29 (±5) hours in patients with advanced breast cancer.

In 6 healthy male subjects given a single oral dose of [ 14 C]palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; feces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine.

The majority of the material was excreted as metabolites.

Age, Gender, and Body Weight Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age range from to 89 years, and body weight range from 37.9 to 123 kg), gender had no effect on the exposure of palbociclib, and age and body weight had no clinically important effect on the exposure of palbociclib.

Data from a pharmacokinetic trial in subjects with varying degrees of hepatic impairment indicate that palbociclib unbound AUC INF decreased 17% in subjects with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, respectively, relative to subjects with normal hepatic function.

Palbociclib unbound

C max increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function.

In addition, based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment based on National Cancer Institute (NCI) classification (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib, further supporting the findings from the dedicated hepatic impairment study.

Data from a pharmacokinetic trial in subjects with varying degrees of renal impairment indicate that palbociclib AUC INF increased by 39%, 42%, and 31% with mild (60 mL/min ≤ CrCl <90 mL/min), moderate (30 mL/min ≤ CrCl <60 mL/min), and severe (CrCl <30 mL/min) renal impairment, respectively, relative to subjects with normal renal function.

Peak palbociclib exposure (C max ) increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function.

In addition, based on a population pharmacokinetic analysis that included 183 patients where 73 patients had mild renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no effect on the exposure of palbociclib.

The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis.

Drug Interactions In vitro data indicate that CYP3A and SULT enzyme SULT2A1 are mainly involved in the metabolism of palbociclib.

Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans.

In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not an inducer of CYP1A2, 2B6, 2C8, and 3A4 at clinically relevant concentrations.

CYP3A Inhibitors: Data from a drug interaction trial in healthy subjects (N=12) indicate that coadministration of multiple 200 mg daily doses of itraconazole with a single 125 mg IBRANCE dose increased palbociclib AUC INF and the C max by approximately 87% and 34%, respectively, relative to a single 125 mg IBRANCE dose given alone.

CYP3A Inducers: Data from a drug interaction trial in healthy subjects (N=15) indicate that coadministration of multiple 600 mg daily doses of rifampin, a strong CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUC INF and C max by 85% and 70%, respectively, relative to a single 125 mg IBRANCE dose given alone.

Data from a drug interaction trial in healthy subjects (N=14) indicate that coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUC INF and C max by 32% and 11%, respectively, relative to a single 125 mg IBRANCE dose given alone.

CYP3A Substrates: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing to steady state in humans.

In a drug interaction trial in healthy subjects (N=26), coadministration of midazolam with multiple doses of IBRANCE increased the midazolam AUC INF and the C max values by 61% and 37%, respectively, as compared to administration of midazolam alone.

Gastric pH Elevating Medications

In a drug interaction trial in healthy subjects, coadministration of a single 125 mg dose of IBRANCE with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions decreased palbociclib C max by 41%, but had limited impact on AUC INF (13% decrease), when compared to a single dose of IBRANCE administered alone.

Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is expected to be minimal.

Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure.

In another healthy subject study, coadministration of a single dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUC INF and C max by 62% and 80%, respectively, when compared to a single dose of IBRANCE administered alone.

In vitro evaluations indicated that palbociclib has a low potential to inhibit the activities of drug transporters organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT)2, and organic anion transporting polypeptide (OATP)1B1, OATP1B3 at clinically relevant concentrations.

In vitro, palbociclib has the potential to inhibit OCT1 at clinically relevant concentrations, as well as the potential to inhibit P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) in the gastrointestinal tract at the proposed dose.

Based on in vitro data, P-gp and BCRP mediated transport are unlikely to affect the extent of o.

• ILD/Pneumonitis Most common adverse reactions (incidence ≥20%) in combination with either letrozole or fulvestrant, including laboratory abnormalities, were white blood cell count decreased, neutrophils decreased, blood creatinine increased, hemoglobin decreased, platelets decreased, infections, aspartate aminotransferase increased, alanine aminotransferase increased, fatigue, nausea, stomatitis, diarrhea, and alopecia.

The most common adverse reactions (incidence ≥20%) in combination with inavolisib and fulvestrant, including laboratory abnormalities, were neutrophils decreased, hemoglobin decreased, fasting glucose increased, platelets decreased, lymphocytes decreased, stomatitis, diarrhea, calcium decreased, fatigue, potassium decreased, creatinine increased, alanine aminotransferase (ALT) increased, nausea, sodium decreased, magnesium decreased, rash, decreased appetite, COVID-19 infection, and headache.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

PALOMA-2: IBRANCE plus Letrozole Patients with estrogen receptor (ER)-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine-based therapy The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus placebo plus letrozole was evaluated in PALOMA-2.

The data described below reflect exposure to IBRANCE in 444 out of 666 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of IBRANCE plus letrozole in PALOMA-2.

The median duration of treatment for

IBRANCE plus letrozole was 19.8 months while the median duration of treatment for placebo plus letrozole arm was 13.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus letrozole.

No dose reduction was allowed for letrozole in PALOMA-2.

Permanent discontinuation associated with an adverse reaction occurred in of 444 (10%) patients receiving IBRANCE plus letrozole and in of 222 (6%) patients receiving placebo plus letrozole.

Adverse reactions leading to permanent discontinuation for patients receiving IBRANCE plus letrozole included neutropenia (1.1%) and alanine aminotransferase increase (0.7%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, fatigue, nausea, alopecia, stomatitis, diarrhea, anemia, rash, asthenia, thrombocytopenia, vomiting, decreased appetite, dry skin, pyrexia, and dysgeusia.

The most frequently reported

Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections, and anemia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus letrozole or placebo plus letrozole in PALOMA-2 are listed in Table 4.

Table 4.

Reactions (≥10%) in PALOMA-2 IBRANCE plus Letrozole (N=444) Placebo plus Letrozole (N=222) Adverse Reaction All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % Grading according to CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable;

Infections and infestations.

Infections includes all reported preferred terms (PTs) that are part of the System Organ Class.

Most common infections (≥1%) include: nasopharyngitis, upper respiratory tract infection, urinary tract infection, oral herpes, sinusitis, rhinitis, bronchitis, influenza, pneumonia, gastroenteritis, conjunctivitis, herpes zoster, pharyngitis, cellulitis, cystitis, lower respiratory tract infection, tooth infection, gingivitis, skin infection, gastroenteritis viral, respiratory tract infection, respiratory tract infection viral, and folliculitis. 6 1 42 3 0 Blood and lymphatic system disorders Neutropenia 80 56 10 6 1 1 Leukopenia 39 24 1 2 0 0 Anemia 24 5 <1 9 2 0 Thrombocytopenia 16 1 <1 1 0 0 Metabolism and nutrition disorders Decreased appetite 15 1 0 9 0 0 Nervous system disorders Dysgeusia 10 0 0 5 0 0 Gastrointestinal disorders Stomatitis Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oral discomfort, oropharyngeal pain, and stomatitis. 30 1 0 14 0 0 Nausea 35 <1 0 26 2 0 Diarrhea 26 1 0 19 1 0 Vomiting 16 1 0 17 1 0 Skin and subcutaneous tissue disorders Alopecia 33 Grade 1 events – 30%; Grade 2 events – 3%.

N/A N/A 16 Grade 1 events – 15%; Grade 2 events – 1%.

N/A N/A Rash Rash includes the following PTs: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, and toxic skin eruption. 18 1 0 12 1 0 Dry skin 12 0 0 6 0 0 General disorders and administration site conditions Fatigue 37 2 0 28 1 0 Asthenia 17 2 0 12 0 0 Pyrexia 12 0 0 9 0 0 Clinically relevant adverse reactions in <10% of patients who received IBRANCE plus letrozole in PALOMA-2 included epistaxis (9%), lacrimation increased (6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%).

Table 5.

Laboratory Abnormalities in

PALOMA-2 IBRANCE plus Letrozole (N=444) Placebo plus Letrozole (N=222) Laboratory Abnormality All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % N=number of patients; WBC=white blood cells.

WBC decreased 97 35 1 25 1 0 Blood creatinine increased 96 2 <1 91 0 0 Neutrophils decreased 95 56 12 20 1 1 Hemoglobin decreased 78 6 0 42 2 0 Platelets decreased 63 1 1 14 0 0 Aspartate aminotransferase increased 52 3 0 34 1 0 Alanine aminotransferase increased 43 2 <1 30 0 0 PALOMA-3: IBRANCE plus Fulvestrant Patients with HR-positive, HER2-negative advanced or metastatic breast cancer who have had disease progression on or after prior adjuvant or metastatic endocrine therapy The safety of IBRANCE (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in PALOMA-3.

The data described below reflect exposure to IBRANCE in 345 out of 517 patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of IBRANCE plus fulvestrant in PALOMA-3.

IBRANCE plus fulvestrant was 10.8 months while the median duration of treatment for placebo plus fulvestrant arm was 4.8 months.

Dose reductions due to an adverse reaction of any grade occurred in 36% of patients receiving IBRANCE plus fulvestrant.

No dose reduction was allowed for fulvestrant in PALOMA-3.

Permanent discontinuation associated with an adverse reaction occurred in of 345 (6%) patients receiving IBRANCE plus fulvestrant, and in of 172 (3%) patients receiving placebo plus fulvestrant.

Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus fulvestrant included fatigue (0.6%), infections (0.6%), and thrombocytopenia (0.6%).

The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus fulvestrant arm by descending frequency were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, diarrhea, thrombocytopenia, vomiting, alopecia, rash, decreased appetite, and pyrexia.

Grade ≥3 adverse reactions (≥5%) in patients receiving IBRANCE plus fulvestrant in descending frequency were neutropenia and leukopenia.

Adverse reactions (≥10%) reported in patients who received IBRANCE plus fulvestrant or placebo plus fulvestrant in PALOMA-3 are listed in Table 6.

Table 6.

Reactions (≥10%) in PALOMA-3 Adverse Reaction IBRANCE plus Fulvestrant (N=345) Placebo plus Fulvestrant (N=172) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 % % % % % % Grading according to CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events; N=number of patients; N/A=not applicable.

Most common infections (≥1%) include: nasopharyngitis, upper respiratory infection, urinary tract infection, bronchitis, rhinitis, influenza, conjunctivitis, sinusitis, pneumonia, cystitis, oral herpes, respiratory tract infection, gastroenteritis, tooth infection, pharyngitis, eye infection, herpes simplex, and paronychia. 3 1 31 3 0 Blood and lymphatic system disorders Neutropenia 83 55 11 4 1 0 Leukopenia 53 30 1 5 1 1 Anemia 30 4 0 13 2 0 Thrombocytopenia 23 2 1 0 0 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 8 1 0 Gastrointestinal disorders Nausea 34 0 0 28 1 0 Stomatitis Stomatitis includes: aphthous stomatitis, cheilitis, glossitis, glossodynia, mouth ulceration, mucosal inflammation, oral pain, oropharyngeal discomfort, oropharyngeal pain, stomatitis. 28 1 0 13 0 0 Diarrhea 24 0 0 19 1 0 Vomiting 19 1 0 15 1 0 Skin and subcutaneous tissue disorders Alopecia 18 Grade 1 events – 17%; Grade 2 events – 1%.

N/A N/A 6 Grade 1 events – 6%.

N/A N/A Rash Rash includes: rash, rash maculo-papular, rash pruritic, rash erythematous, rash papular, dermatitis, dermatitis acneiform, toxic skin eruption. 17 1 0 6 0 0 General disorders and administration site conditions Fatigue 41 2 0 29 1 0 Pyrexia 13 <1 0 5 0 0 Clinically relevant adverse reactions in <10% of patients who received IBRANCE plus fulvestrant in PALOMA-3 included asthenia (8%), dysgeusia (7%), epistaxis (7%), lacrimation increased (6%), dry skin (6%), vision blurred (6%), dry eye (3.8%), and febrile neutropenia (0.9%).

Table 7.

PALOMA-3 Laboratory Abnormality IBRANCE plus Fulvestrant (N=345) Placebo plus Fulvestrant (N=172) All Grades % Grade 3 % Grade 4 % All Grades % Grade 3 % Grade 4 % N=number of patients; WBC=white blood cells.

WBC decreased 99 45 1 26 0 1 Neutrophils decreased 96 56 11 14 0 1 Blood creatinine increased 95 1 0 82 0 0 Hemoglobin decreased 78 3 0 40 2 0 Platelets decreased 62 2 1 10 0 0 Aspartate aminotransferase increased 43 4 0 48 4 0 Alanine aminotransferase increased 36 2 0 34 0 0 INAVO120: IBRANCE plus Inavolisib and Fulvestrant Adults with PIK3CA-mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer whose disease progressed during or within 12 months of completing adjuvant endocrine therapy and who have not received prior systemic therapy for locally advanced or metastatic disease The safety of the combination of IBRANCE plus inavolisib and fulvestrant was evaluated in a randomized, double-blind, placebo-controlled study (INAVO120) in 324 patients with PIK3CA -mutated, HR-positive, HER2-negative, locally advanced or metastatic breast cancer.

Patients received either

IBRANCE 125 mg orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a cycle of 28 days plus fulvestrant in combination with inavolisib (n=162) or placebo (n=162).

IBRANCE plus inavolisib and fulvestrant was 9 months (range: 0 to 39 months).

Serious adverse reactions occurred in 24% of patients who received IBRANCE plus inavolisib and fulvestrant.

Serious adverse reactions occurring in ≥1% of patients receiving IBRANCE plus inavolisib and fulvestrant included anemia (1.9%), diarrhea (1.2%), and urinary tract infection (1.2%).

Fatal adverse reactions occurred in 3.7% of patients who received IBRANCE plus inavolisib and fulvestrant, including (0.6% each) acute coronary syndrome, cerebral hemorrha.

capsules are taken orally with food in combination with an aromatase inhibitor, fulvestrant, or inavolisib and fulvestrant.

• Recommended starting dose: 125 mg once daily taken with food for 21 days followed by 7 days off treatment.

• Dosing interruption and/or dose reductions are recommended based on individual safety and tolerability. 2.1 Recommended Dose and Schedule The recommended dose of IBRANCE 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.

IBRANCE capsule should be taken with food.

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.

Information of fulvestrant.

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 capsules should be swallowed whole (do not chew, crush, or open them prior to swallowing).

Capsules 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 or IBRANCE plus inavolisib and fulvestrant therapy 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 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.

Grade 1 or 2 No dose adjustment is required.

Grade 3 Day 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 of first 2 cycles: If Grade on Day 15, continue IBRANCE at current dose to complete cycle and repeat complete blood count on Day 22.

If Grade 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 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 ºC and/or infection At any time: Withhold IBRANCE until recovery to Grade ≤2.

Resume at the next lower dose.

Grade At any time

Withhold IBRANCE until recovery to Grade ≤2.

Table 3.

Management – Non-Hematologic Toxicities CTCAE Grade Dose Modifications Grading according to CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events.

• 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.

Information for coadministered endocrine therapy and/or inavolisib dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

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 to 5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor.

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.

is supplied in the following strengths and package configurations: IBRANCE Capsules Package Configuration Capsule Strength (mg) NDC Capsule Description Bottles of 21 capsules 125 NDC 0069-0189-21 opaque, hard gelatin capsules, size 0, with caramel cap and body, printed with white ink "Pfizer" on the cap, "PBC 125" on the body Bottles of 21 capsules 100 NDC 0069-0188-21 opaque, hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink "Pfizer" on the cap, "PBC 100" on the body Bottles of 21 capsules 75 NDC 0069-0187-21 opaque, hard gelatin capsules, size 2, with light orange cap and body, printed with white ink "Pfizer" on the cap, "PBC 75" on the body Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Store at 20 °C to 25 °C (68 °F to 77 °F); excursions permitted between 15 °C to 30 °C (59 °F to 86 °F) .

Based on findings from animal studies and its mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman.

There are no available data in pregnant women to inform the drug-associated risk.

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 AUC.

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown.

In the

U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

In a fertility and early embryonic development study in female rats, palbociclib was administered orally for 15 days before mating through to Day of pregnancy, which did not cause embryo toxicity at doses up to 300 mg/kg/day with maternal systemic exposures approximately 4 times the human exposure (AUC) at the recommended dose.

In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of palbociclib up to 300 mg/kg/day and 20 mg/kg/day, respectively, during the period of organogenesis.

The maternally toxic dose of 300 mg/kg/day was fetotoxic in rats, resulting in reduced fetal body weights.

At doses ≥100 mg/kg/day in rats, there was an increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra).

At the maternally toxic dose of 20 mg/kg/day in rabbits, there was an increased incidence of skeletal variations, including small phalanges in the forelimb.

At 300 mg/kg/day in rats and 20 mg/kg/day in rabbits, the maternal systemic exposures were approximately and 9 times the human exposure (AUC) at the recommended dose, respectively.

CDK4/6 double knockout mice have been reported to die in late stages of fetal development (gestation Day 14.5 until birth) due to severe anemia.

However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.

The safety and effectiveness of

IBRANCE in pediatric patients have not been established.

IBRANCE were assessed but not established in three trials: one open-label trial [A5481092, (NCT03709680)] that included 98 pediatric patients to <17 years of age who received IBRANCE in combination with chemotherapy for recurrent or refractory solid tumors and two open-label trials that included 42 pediatric patients to <17 years of age who received IBRANCE as a single agent for recurrent or refractory solid tumors [APEC1621I, (NCT03526250)] or primary central nervous system (CNS) tumors [PBTC-042, (NCT02255461). No new safety signals were observed in these trials. Palbociclib exposures in pediatric patients who received IBRANCE as a single agent or in combination were within range of those observed in adults given a similar dose based on body surface area. Juvenile Animal Toxicity Data Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), kidney (tubule vacuolation, chronic progressive nephropathy) and adipose tissue (atrophy) were identified in a 27 week repeat-dose toxicology study in rats that were immature at the beginning of the studies and were most prevalent in males at oral palbociclib doses ≥30 mg/kg/day (approximately 11 times the adult human exposure [AUC] at the recommended dose).

Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present with lower incidence and severity in a 15 week repeat-dose toxicology study in immature rats.

Altered glucose metabolism or associated changes in the pancreas, eye, kidney and adipose tissue were not identified in a 27-week repeat-dose toxicology study in rats that were mature at the beginning of the study and in dogs in repeat-dose toxicology studies up to 39 weeks duration.

Toxicities in teeth independent of altered glucose metabolism were observed in rats.

Administration of 100 mg/kg palbociclib for 27 weeks (approximately 15 times the adult human exposure [AUC] at the recommended dose) resulted in abnormalities in growing incisor teeth (discolored, ameloblast degeneration/necrosis, mononuclear cell infiltrate).

Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals.

Of 444 patients who received IBRANCE in PALOMA-2, 181 patients (41%) were ≥65 years of age and 48 patients (11%) were ≥75 years of age.

Of 347 patients who received IBRANCE in PALOMA-3, 86 patients (25%) were ≥65 years of age and 27 patients (8%) were ≥75 years of age.

No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients.