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 should be taken with food [see Clinical Pharmacology (12.3)].

When coadministered with palbociclib, the recommended dose of letrozole is 2.5 mg taken once daily continuously throughout the 28-day cycle. Please refer to the full prescribing information of letrozole.

When coadministered with palbociclib, 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.

Patients should be encouraged 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 fulvestrant therapy should be treated with luteinizing hormone-releasing hormone (LHRH) agonists 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.

Refer to the full prescribing information for coadministered endocrine therapy dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications.

5.1 Neutropenia

Neutropenia was the most frequently reported adverse reaction in both Study 1 (75%) and Study 2 (83%). A Grade ≥3 decrease in neutrophil counts was reported in 62% of patients receiving IBRANCE plus letrozole in Study 1 and 66% of patients receiving IBRANCE plus fulvestrant in Study 2. 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 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 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 [see Dosage and Administration (2.2)].

Febrile neutropenia has been reported in about 1% of patients exposed to IBRANCE. One death due to neutropenic sepsis was observed in Study 2. Physicians should inform patients to promptly report any episodes of fever [see Patient Counseling Information (17)].

5.2 Pulmonary Embolism

Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole in Study 1 (5%) and in patients treated with IBRANCE plus fulvestrant in Study 2 (1%) compared with no cases in patients treated either with letrozole alone or fulvestrant plus placebo. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate.

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)].

6.1 Clinical Studies Experience

Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

7.1 Agents That May Increase Palbociclib Plasma Concentrations

7.2 Agents That May Decrease Palbociclib Plasma Concentrations

7.3 Drugs That May Have Their Plasma Concentrations Altered by Palbociclib

Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with 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 IBRANCE may increase their exposure [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

The safety and efficacy of IBRANCE in pediatric patients have not been studied.

8.5 Geriatric Use

Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. Of 347 patients who received IBRANCE in Study 2, 86 patients (25%) were ≥65 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients.

8.6 Hepatic Impairment

Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (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. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].

8.7 Renal Impairment

Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Palbociclib is an inhibitor of cyclin-dependent kinase (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 protein (Rb) 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 leads to increased cell senescence, which was sustained for up to 6 days following drug removal. 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.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The pharmacokinetics (PK) of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies have not been conducted with palbociclib.

Palbociclib was aneugenic in Chinese Hamster Ovary cells in vitro and in the bone marrow of male rats at doses ≥100 mg/kg/day for 3 weeks. Palbociclib was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay and was not clastogenic in the in vitro human lymphocyte chromosome aberration assay.

In a fertility study in female rats, palbociclib did not affect mating or fertility at any dose up to 300 mg/kg/day (approximately 4 times human clinical exposure based on AUC) and no adverse effects were observed in the female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the rat and 3 mg/kg/day in the dog (approximately 6 times and similar to human exposure [AUC], at the recommended dose, respectively).

The adverse effects of palbociclib on male reproductive function and fertility were observed in the repeat-dose toxicology studies in rats and dogs and a male fertility study in rats. In repeat-dose toxicology studies, palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle at ≥30 mg/kg/day in rats and ≥0.2 mg/kg/day in dogs included decreased organ weight, atrophy or degeneration, hypospermia, intratubular cellular debris, lower sperm motility and density, and decreased secretion. Partial reversibility of male reproductive organ effects was observed in the rat and dog following a 4- and 12-week non-dosing period, respectively. These doses in rats and dogs resulted in approximately ≥10 and 0.1 times, respectively, the exposure [AUC] in humans at the recommended dose. In the fertility and early embryonic development study in male rats, palbociclib caused no effects on mating but resulted in a slight decrease in fertility at 100 mg/kg/day with projected exposure levels [AUC] of 20 times the exposure in humans at the recommended dose.

13.2 Animal Toxicology and/or Pharmacology

Altered glucose metabolism (glycosuria, hyperglycemia, decreased insulin) associated with changes in the pancreas (islet cell vacuolation), eye (cataracts, lens degeneration), teeth (degeneration/necrosis of ameloblasts in actively growing teeth), kidney (tubule vacuolation, chronic progressive nephropathy), and adipose tissue (atrophy) were identified in the 27-week repeat-dose toxicology study in rats and were most prevalent in males at doses ≥30 mg/kg/day (approximately 11 times the human exposure [AUC] at the recommended dose). Some of these findings (glycosuria/hyperglycemia, pancreatic islet cell vacuolation, and kidney tubule vacuolation) were present in the 15-week repeat-dose toxicology study in rats, but with lower incidence and severity. The rats used in these studies were approximately 7 weeks old at the beginning of the studies. Altered glucose metabolism or associated changes in pancreas, eye, teeth, kidney, and adipose tissue were not identified in dogs in repeat-dose toxicology studies up to 39 weeks duration.

Study 1: IBRANCE plus Letrozole

Patients with ER-positive, HER2-negative advanced or metastatic breast cancer for initial endocrine based therapy

Study 1 was a randomized, open-label, multicenter study of IBRANCE plus letrozole versus letrozole alone conducted in postmenopausal women with ER-positive, HER2-negative advanced breast cancer who had not received previous systemic treatment for their advanced disease. A total of 165 patients were randomized in Study 1. Randomization was stratified by disease site (visceral versus bone only versus other) and by disease-free interval (>12 months from the end of adjuvant treatment to disease recurrence versus ≤12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease). IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Patients received study treatment until progressive disease, unmanageable toxicity, or consent withdrawal. The major efficacy outcome measure of the study was investigator-assessed PFS evaluated according to Response Evaluation Criteria in Solid Tumors Version 1.0 (RECIST).

Patients enrolled in this study had a median age of 63 years (range 38 to 89). The majority of patients were White (90%) and all patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. Forty-three percent of patients had received chemotherapy and 33% had received antihormonal therapy in the neoadjuvant or adjuvant setting prior to their diagnosis of advanced breast cancer. Forty-nine percent of patients had no prior systemic therapy in the neoadjuvant or adjuvant setting. The majority of patients (98%) had metastatic disease. Nineteen percent of patients had bone only disease and 48% of patients had visceral disease.

Major efficacy results from Study 1 are summarized in Table 8 and Figure 1. Consistent results were observed across patient subgroups of, disease-free interval, disease site and prior therapy. The treatment effect of the combination on PFS was also supported by a retrospective independent review of radiographs with an observed hazard ratio (HR) of 0.621 (95% CI: 0.378, 1.019). Overall response rate in patients with measurable disease as assessed by the investigator was higher in the IBRANCE plus letrozole compared to the letrozole-alone arm (55.4% versus 39.4%). At the time of the final analysis of PFS, overall survival (OS) data were not mature with 37% of events.

Table 8. Efficacy Results – Study 1 (Investigator Assessment, Intent-to-Treat Population)

	IBRANCE plus Letrozole (N=84)	Letrozole (N=81)
CI=confidence interval; N=number of patients.
Progression-Free Survival (PFS) Number of PFS Events (%)	41 (48.8%)	59 (72.8%)
Hazard ratio (95% CI)	0.488 (0.319, 0.748)
Median PFS [months] (95% CI)	20.2 (13.8, 27.5)	10.2 (5.7, 12.6)

Figure 1. Kaplan-Meier Curves of Progression-Free Survival – Study 1 (Investigator Assessment, Intent-to-Treat Population)

LET=letrozole; PAL=palbociclib.

Study 2: 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

Study 2 was an international, randomized, double-blind, parallel group, multicenter study of IBRANCE plus fulvestrant versus placebo plus fulvestrant conducted in women with HR-positive, HER2-negative advanced breast cancer, regardless of their menopausal status, whose disease progressed on or after prior endocrine therapy. A total of 521 pre/postmenopausal women were randomized 2:1 to IBRANCE plus fulvestrant or placebo plus fulvestrant and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal), and presence of visceral metastases. IBRANCE was given orally at a dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment. Pre/perimenopausal women were enrolled in the study and received the LHRH agonist goserelin for at least 4 weeks prior to and for the duration of Study 2. Patients continued to receive assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. The major efficacy outcome of the study was investigator-assessed PFS evaluated according to RECIST 1.1.

Patients enrolled in this study had a median age of 57 years (range 29 to 88). The majority of patients on study were White (74%), all patients had an ECOG PS of 0 or 1, and 80% were postmenopausal. All patients had received prior systemic therapy and 75% of patients had received a previous chemotherapy regimen. Twenty-five percent of patients had received no prior therapy in the metastatic disease setting, 60% had visceral metastases, and 23% had bone only disease.

The results from the investigator-assessed PFS from Study 2 are summarized in Table 9 and Figure 2. Consistent results were observed across patient subgroups of disease site, sensitivity to prior hormonal therapy and menopausal status. Confirmed overall response rate in patients with measurable disease as assessed by the investigator was 24.6% in the IBRANCE plus fulvestrant and was 10.9% in the placebo plus fulvestrant arm. Duration of response was 9.3 months in the IBRANCE plus fulvestrant arm compared with 7.6 months in the placebo plus fulvestrant arm. At the time of final analysis of PFS, OS data were not mature with 29% of events.

Table 9. Efficacy Results – Study 2 (Investigator Assessment, Intent-to-Treat Population)

	IBRANCE plus Fulvestrant (N=347)	Placebo plus Fulvestrant (N=174)
CI=confidence interval; N=number of patients
Progression-Free Survival   Number of PFS Events (%)	145 (41.8%)	114 (65.5%)
Hazard ratio (95% CI) and p-value	0.461 (0.360-0.591), p<0.0001
Median PFS [months] (95% CI)	9.5 (9.2-11.0)	4.6 (3.5-5.6)

Figure 2. Kaplan-Meier Plot of Progression-Free Survival (Investigator Assessment, Intent-to-Treat Population) – Study 2

FUL=fulvestrant; PAL=palbociclib; PCB=placebo.

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).

Myelosuppression/Infection

• Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions (5.1)].

Pulmonary Embolism

• Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions (5.2)].

Drug Interactions

• Grapefruit may interact with IBRANCE. Patients should not consume grapefruit products while on treatment with IBRANCE.
• Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers.
• Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions (7)].

Dosing and Administration

• Advise patients to take IBRANCE with food.
• 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). No capsule should be ingested if it is broken, cracked, or otherwise not intact.

Pregnancy, Lactation, and Fertility

• Embryo-Fetal Toxicity
  • Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment with IBRANCE therapy and for at least 3 weeks after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1 and 8.3)].
  • Advise male patients with female partners of reproductive potential to use effective contraception during treatment with IBRANCE and for at least 3 months after the last dose [see Use in Specific Populations (8.3)].
• Lactation: Advise women not to breastfeed during treatment with IBRANCE and for 3 weeks after the last dose [see Use in Specific Populations (8.2)].