Ibrance

Ibrance

palbociclib

Manufacturer:

Pfizer
The information highlighted (if any) are the most recent updates for this brand.
Full Prescribing Info
Contents
Palbociclib.
Description
Each capsule contains 75 mg or 100 mg or 125 mg of palbociclib freebase.
Palbociclib is a yellow to orange powder with a pKa of 7.4 (the secondary piperazine nitrogen) and 3.9 (the pyridine nitrogen).
Excipients/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.
Action
Pharmacology: Pharmacodynamics: Mechanism of action: Palbociclib is a highly selective, reversible inhibitor of cyclin-dependent kinases (CDK) 4 and 6. Cyclin D1 and CDK4/6 are downstream of multiple signaling pathways which lead to cellular proliferation.
Pharmacodynamic effects: Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking progression of the cell from G1 into S phase of the cell cycle. Testing of palbociclib in a panel of molecularly profiled breast cancer cell lines revealed high efficacy against luminal breast cancers, particularly estrogen receptor (ER)-positive breast cancers. In the cell lines tested, the loss of retinoblastoma (Rb) was associated with loss of palbociclib activity. Available clinical data are reported in the clinical efficacy and safety section (see Pharmacodynamics as previously mentioned). Mechanistic analyses revealed that the combination of palbociclib with anti-estrogen agents enhanced the re-activation of retinoblastoma (Rb) through inhibition of Rb phosphorylation resulting in reduced E2F signaling and growth arrest. In vivo studies using a patient derived ER-positive breast cancer xenograft model (HBCx-34) demonstrated that the combination of palbociclib and letrozole further enhanced inhibition of Rb phosphorylation, downstream signaling, and dose-dependent tumor growth. Studies are ongoing investigating the importance of Rb expression for the activity of palbociclib in fresh tumour samples.
Cardiac electrophysiology: The effect of palbociclib on the QT interval corrected for heart rate (QTc) interval was evaluated using time matched electrocardiogram (ECG) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with advanced breast cancer. Palbociclib did not prolong the QTc to any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).
Clinical trial efficacy: Study 1: The efficacy of palbociclib was evaluated in a randomized, open-label, multicenter study of palbociclib plus letrozole versus letrozole alone conducted in postmenopausal women with ER-positive, HER2-negative locally advanced or metastatic breast cancer.
The study was comprised of a limited Phase 1 portion (N = 12), designed to confirm the safety and tolerability of the combination palbociclib plus letrozole, followed by a randomized Phase 2 portion (N = 165), designed to evaluate the efficacy and safety of palbociclib in combination with letrozole compared with letrozole alone in the first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer.
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).
The patient demographic and baseline characteristics were generally balanced between the study arms in terms of age, race, disease sites, stage, and prior therapies.
The primary endpoint of the study was investigator-assessed progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0.
The median PFS (mPFS) for patients in the palbociclib plus letrozole arm was 20.2 months (95% confidence interval [CI]: 13.8, 27.5) and 10.2 months (95% CI: 5.7, 12.6) for patients in the letrozole-alone arm. The observed hazard ratio (HR) was 0.488 (95% CI: 0.319, 0.748) in favor of palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of 0.0004.
At the final overall survival (OS) analysis, the observed HR was 0.897 (95% CI: 0.623, 1.294) with a stratified 1-sided p-value of 0.2812. The median OS in the palbociclib plus letrozole arm was 37.5 months (95% CI: 31.4, 47.8) and in the letrozole alone arm was 34.5 months (95% CI: 27.4, 42.6).
The estimated survival probabilities at 12, 24, and 36 months between the 2 treatment arms were 89.0% versus 87.0%, 77.9% versus 71.1%, and 50.8% versus 47.4%, in favor of palbociclib plus letrozole, respectively.
Study 2: The efficacy of palbociclib in combination with letrozole versus letrozole plus placebo was evaluated in an international, randomized, double-blind, placebo-controlled, parallel-group, multicenter study conducted in women with ER-positive, HER2-negative locally advanced or metastatic breast cancer (PALOMA-2) who had not received prior systemic treatment for their advanced disease.
A total of 666 postmenopausal women were randomized 2:1 to either the palbociclib plus letrozole arm or to the placebo plus letrozole arm and were stratified by site of disease (visceral, non-visceral), disease-free interval from the end of (neo)adjuvant treatment to disease recurrence (de novo metastatic, ≤12 months from the end of adjuvant treatment to disease recurrence, >12 months from the end of adjuvant treatment to disease recurrence), and by the type of prior (neo)adjuvant anticancer therapies (prior hormonal therapy, no prior hormonal therapy). Patients with advanced symptomatic, visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement), were not eligible for enrolment into the study.
Patients continued to receive their assigned treatment until objective disease progression, symptomatic deterioration, unacceptable toxicity, death, or withdrawal of consent, whichever occurred first. Crossover between treatment arms was not allowed.
Patients were well matched for baseline demographics and disease characteristics between the palbociclib plus letrozole arm and the placebo plus letrozole arm. The median age of patients enrolled in this study was 62 years (range 28-89); 48.3% of patients had received chemotherapy and 56.3% had received antihormonal therapy in the (neo)adjuvant setting prior to their diagnosis of advanced breast cancer, while 37.2% of patients had received no prior systemic therapy in the (neo)adjuvant setting. Most patients (97.4%) had metastatic disease at baseline; 22.7% of patients had bone only disease and 49.2% of patients had visceral disease.
The primary endpoint of the study was PFS evaluated according to RECIST version 1.1 as assessed by investigator. Secondary efficacy endpoints included objective response (OR), duration of response (DOR), clinical benefit response (CBR), overall survival (OS), safety, EQ-5D scores and health-related quality of life (QoL) assessed using the FACT-B questionnaire.
The study met its primary objective of improving PFS. The estimated HR was 0.576 (95% CI: 0.463, 0.718) in favor of palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of <0.000001. The mPFS for patients in the palbociclib plus letrozole arm was 24.8 months (95% CI: 22.1, Not estimable [NE]) and 14.5 months (95% CI: 12.9, 17.1) for patients in the placebo plus letrozole arm. The treatment effect of the combination on PFS was also supported by an independent review of radiographs with an estimated HR of 0.653 (95% CI: 0.505, 0.844).
Efficacy data from the PALOMA-2 study are summarized in Table 1 and the Kaplan-Meier curve for PFS is shown in the figure. (See Table 1 and figure.)


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A series of prespecified subgroup PFS analyses was performed based on baseline demographic and disease characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease progression or death in the palbociclib plus letrozole arm was observed in all individual patient subgroups defined by stratification factors and baseline characteristics in the primary and in the updated analyses. Patients with advanced, symptomatic visceral spread at risk of life-threatening complications in the short term were not included in PALOMA-2. Objective Response Rate (ORR) was higher in patients with visceral disease treated with palbociclib plus letrozole compared to placebo plus letrozole (58.9% [95% CI: 52.0, 65.5], versus 45.5% [95% CI: 35.9, 55.2], respectively), while in patients with non visceral metastases (n= 342, of whom 151 had bone only disease) ORR was comparable between treatment groups (34.8% [95% CI: 28.6, 41.3], versus 31.3% [95% CI: 22.8, 40.7]) The overall survival (OS) data were not mature at the time of the final PFS analysis (20% of patients had died). Patients will continue to be followed for the final analysis.
An analysis of time-to-deterioration composite endpoint (TTD) in Functional Assessment of Cancer Therapy-Breast (FACT-B), defined as the time between baseline and first occurrence of decrease of ≥7 points in FACT-B scores, was carried out based on survival analysis methods using a Cox proportional hazards model and log-rank test. No statistically significant difference was observed in TTD in FACT-B total scores between the palbociclib plus letrozole arm and the placebo plus letrozole arm (HR of 1.042 [95% CI: 0.838, 1.295]; 1-sided p-value=0.663.
Pharmacokinetics: The pharmacokinetics of palbociclib were characterized in patients with solid tumors including advanced breast cancer and in healthy subjects.
Absorption: The mean time to Cmax (Tmax) of palbociclib is generally between 6 to 12 hours following oral administration. The mean absolute bioavailability of palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increase proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulates with a median accumulation ratio of 2.4 (range 1.5-4.2).
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 palbociclib given under overnight fasted conditions, the AUCinf and Cmax of palbociclib increased by 21% and 38% when given with high-fat food, by 12% and 27% when given with low-fat food, and by 13% and 24% when moderate-fat food was given 1 hour before and 2 hours after palbociclib dosing. In addition, food intake significantly reduced the intersubject and intrasubject variability of palbociclib exposure. Based on these results, palbociclib should be taken with food.
Gastric pH elevating medication effect: In a healthy subject study, coadministration of a single 125 mg dose of IBRANCE with multiple doses of the PPI rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when compared to a single 125 mg 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 125 mg dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared with a single dose of IBRANCE administered alone.
Distribution: Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence over the concentration range of 500 ng/mL to 5000 ng/mL. The mean fraction unbound (fu) of palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function. The geometric mean apparent volume of distribution (Vz/F) was 2583 (26%) L.
Metabolism: In vitro and in vivo studies indicate that palbociclib undergoes extensive hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C] palbociclib to humans, the major 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. The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. The majority of the material was excreted as metabolites. In feces, the sulfamic acid conjugate of palbociclib was the major drug-related component, accounting for 25.8% of the administered dose. In vitro studies with human hepatocytes, liver cytosolic and S9 fractions, and recombinant sulfotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.
Elimination: The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.08 L/h, and the mean plasma elimination half-life was 28.8 hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C] 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. Excretion of unchanged palbociclib in feces and urine was 2.3% and 6.9% of the administered dose, respectively.
Age, gender, and body weight: Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 female patients, age ranging from 22 to 89 years, and body weight ranging 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.
Pediatric population: Pharmacokinetics of palbociclib have not been evaluated in patients ≤18 years of age.
Elderly population: Of 444 patients who received IBRANCE in Study A5481008 (PALOMA-2), 181 patients (41%) were ≥65 years of age with 133 (30%) patients between the age of 65 and 74, and 48 (11%) patients ≥75 years of age. Of 347 patients who received IBRANCE in Study A5481023 (PALOMA-3), 86 patients (25%) were ≥65 years of age with 59 (17%) patients between the age of 65 and 74, and 27 (8%) patients ≥75 years of age. No overall differences in safety were observed across all age groups and elderly age groups. Neutropenia was the most common adverse event with palbociclib across all age groups; however, the incidence of febrile neutropenia was low in all age groups.
Hepatic impairment: Data from a pharmacokinetic trial in subjects with varying degrees of hepatic function indicate that palbociclib unbound exposure (unbound AUCinf) decreased by 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 hepatic impairment (Child-Pugh class C), respectively, relative to subjects with normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax) was 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 with advanced cancer where 40 patients had mild hepatic impairment based on National Cancer institute (NCI) classification (total bilirubin ≤Upper Limit of Normal (ULN) and Aspartate Aminotransferase (AST) >ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST), mild hepatic impairment had no effect on the pharmacokinetics (PK) of palbociclib.
Renal impairment: Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total palbociclib exposure (AUCinf) was 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 (CrCl ≥90 mL/min) renal function. Peak palbociclib exposure (Cmax) was 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 with advanced cancer where 73 patients had mild renal impairment and 29 patients had moderate renal impairment, mild and moderate renal impairment had no effect on the PK of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring hemodialysis.
Asian race: In a dedicated PK study in healthy volunteers, palbociclib geometric mean AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese subjects compared with non-Asian subjects after a single oral dose. However, this finding was not reproduced consistently in subsequent studies in breast cancer patients after multiple dosing. Based on an analysis of the cumulative pharmacokinetic, safety, and efficacy data, no dose adjustment based on Asian race is necessary.
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 did not prolong QTc to any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).
Toxicology: Preclinical safety data: The primary target organ findings following single and/or repeat dosing included hematolymphopoietic and male reproductive organ effects in rats and dogs, and effects on bone and actively growing incisors in rats only. These systemic toxicities were generally observed at clinically relevant exposures based on AUC. Partial to full reversal of effects on the hematolymphopoietic, male reproductive systems, and incisor teeth were established, whereas the bone effect was not reversed following a 12-week nondosing period. In addition, cardiovascular effects (QTc prolongation, decreased heart rate, and increased RR interval and systolic blood pressure) were identified in telemetered dogs at ≥4 times human clinical exposure based on Cmax.
Carcinogenicity: The relevance of the male rat neoplastic finding to humans is unknown.
Genotoxicity: Palbociclib was not mutagenic in a bacterial reverse mutation (Ames) assay and did not induce structural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay.
Palbociclib induced micronuclei via an aneugenic mechanism in Chinese Hamster Ovary cells in vitro and in the bone marrow of male rats at doses ≥100 mg/kg/day. The no observed effect level for aneugenicity was approximately 7 times human clinical exposure based on AUC.
Impairment of fertility: Palbociclib did not affect mating or fertility in female rats at any dose tested up to 300 mg/kg/day (approximately 3 times human clinical exposure based on AUC) and no adverse effects were observed in 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 5 and 3 times human clinical exposure based on AUC, respectively).
Palbociclib is considered to have the potential to impair reproductive function and fertility in male humans based on nonclinical findings in rats and dogs. Palbociclib-related findings in the testis, epididymis, prostate, and seminal vesicle included decreased organ weight, atrophy or degeneration, hypospermia, intratubular cellular debris, lower sperm motility and density, and decreased secretion. These findings were observed in rats and/or dogs at exposures ≥9 times or subtherapeutic compared to human clinical exposure based on AUC. Partial reversibility of male reproductive organ effects was observed in the rat and dog following a 4- and 12-week non-dosing period, respectively. Despite these male reproductive organ findings, there were no effects on mating or fertility in male rats at projected exposure levels 13 times human clinical exposure based on AUC.
Developmental toxicity:
Palbociclib was fetotoxic in pregnant animals. An increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra) at ≥100 mg/kg/day was observed in rats. Reduced fetal body weights were observed at a maternally toxic dose of 300 mg/kg/day in rats (3 times human clinical exposure based on AUC), and an increased incidence of skeletal variations, including small phalanges in the forelimb was observed at a maternally toxic dose of 20 mg/kg/day in rabbits (4 times human clinical exposure based on AUC). Actual fetal exposure and cross-placenta transfer have not been examined.
Indications/Uses
IBRANCE in combination with letrozole is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer with proven diagnosis of adenocarcinoma of the breast with evidence of loco regionally recurrent or metastatic disease not amenable to resection or radiation.
In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
Dosage/Direction for Use
The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days.
When coadministered with palbociclib, the recommended dose of letrozole is 2.5 mg taken orally once daily continuously throughout the 28-day cycle. Please refer to the full prescribing information of letrozole.
Treatment of pre/perimenopausal women with the combination of palbociclib plus an aromatase inhibitor should always be combined with an LHRH agonist (see Precautions).
Patients should be encouraged to take their dose at approximately the same time each day. Continue the treatment as long as the patient is deriving clinical benefit from therapy.
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.
Method of administration: IBRANCE is for oral use. It should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see Pharmacology: Pharmacokinetics under Actions). Palbociclib should not be taken with grapefruit or grapefruit juice (see Interactions). IBRANCE capsules should be swallowed whole (should not be chewed, crushed, or opened prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact.
Dose modifications: Dose modification of IBRANCE is recommended based on individual safety and tolerability.
Management of some adverse reactions may require temporary dosing interruptions/cycle delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 2, 3, and 4 (see Precautions and Adverse Reactions). (See Table 2, Table 3 and Table 4.)


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No dose modifications are required on the basis of patient's age, sex, or body weight (see Pharmacology: Pharmacokinetics under Actions). Permanently discontinue IBRANCE in patients with severe interstitial lung disease (ILD) or pneumonitis.
Special populations: Elderly population: No dose adjustment is necessary in patients ≥65 years of age (see Pharmacology: Pharmacokinetics under Actions).
Pediatric population: The safety and efficacy of IBRANCE in children and adolescents ≤18 years of age have not been established.
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 on Schedule 3/1 (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is required for patients with mild, moderate or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min). Insufficient data are available in patients requiring hemodialysis to provide any dosing recommendation in this patient population (see Pharmacology: Pharmacokinetics under Actions).
Overdosage
In the event of a palbociclib overdose, both gastrointestinal (e.g., nausea, vomiting) and haematological (e.g., neutropenia) toxicity may occur. There is no known antidote for palbociclib. The treatment of IBRANCE overdose should consist of general supportive measures.
Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Use of preparations containing St. John's Wort (see Interactions).
Special Precautions
Myelosuppression: Neutropenia: Decreased neutrophil counts have been observed very commonly in clinical studies with IBRANCE. In patients receiving IBRANCE in combination with letrozole (PALOMA-1 and PALOMA-2), Grade 3 (ANC 500 <1000/mm3) and Grade 4 (ANC <500/mm3) decreased neutrophil counts were reported.
In PALOMA-1 and PALOMA-2 the median time to first episode of any grade neutropenia was 15 days (12-700 days) and 28 days (range 12-854) for Grade ≥3 neutropenia. The median duration of Grade ≥3 neutropenia was 33 days (range 1-534).
An increase in palbociclib exposure has been associated with more severe neutropenia; in Asian subjects, frequency of Grade ≥3 neutropenia is higher than in White subjects (see Pharmacology: Pharmacokinetics: Special Populations: Asian race under Actions). Febrile neutropenia has been reported in 1.6% of patients receiving palbociclib in combination with letrozole in PALOMA-2. Febrile neutropenia has not been reported in PALOMA-1. Febrile neutropenia has been reported in about 2% of patients exposed to IBRANCE across the overall clinical program (see Infections as follows).
Monitor complete blood count 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.
Dosing interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see Table 3 under Dosage & Administration).
Anaemia: Anaemia has been observed very commonly in clinical studies with IBRANCE. In patients receiving IBRANCE in combination with letrozole (PALOMA-1 and PALOMA-2), Grade 3 and Grade 4 anaemia was observed. In PALOMA-1 and PALOMA-2 the median time to first episode of any grade anaemia was 29 days (range 1-777 days) and 195 days (range 14-760) for Grade ≥3 anaemia. The median duration of Grade ≥3 anaemia was 7 days (range 1-125). Across both studies, supportive treatment with red blood cell growth factors and transfusions was administered.
Thrombocytopenia: Thrombocytopenia has been observed very commonly in clinical studies with IBRANCE. In patients receiving IBRANCE in combination with letrozole (PALOMA-1 and PALOMA-2), Grade 3 and Grade 4 thrombocytopenia was observed. In PALOMA-1 and PALOMA-2 the median time to first episode of any grade thrombocytopenia was 27 days (range 2-875 days) and 256 days (range 21-652 days) for Grade ≥3 thrombocytopenia. The median duration of Grade ≥3 thrombocytopenia was 7 days (range 1-28 days).
Interstitial lung disease/pneumonitis: Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin-dependent kinase 4/6 (CDK 4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical trials, 1.4% of IBRANCE-treated patients had ILD/pneumonitis of any grade, 0.1% had grade 3, and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting (see Adverse Reactions), with fatalities reported. 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 ILD/pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently discontinue IBRANCE in patients with severe ILD or pneumonitis (see Dosage & Administration).
Infections: Since IBRANCE has myelosuppressive properties, it may predispose to infections.
Infections have been reported at a higher rate in patients treated with IBRANCE in randomized clinical studies compared to patients treated in the respective comparator arm. Grades 3 and 4 infections occurred in 4.4% and 0.7%, respectively, in patients treated with IBRANCE in either combination compared to patients treated in the respective comparator arms (2.5% and 0%, respectively).
Monitor patients for signs and symptoms of infection and treat as medically appropriate (see Adverse Reactions).
Physicians should inform patients to promptly report any episodes of fever.
Pre/perimenopausal women: Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausal women are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist.
Critical visceral disease: The efficacy and safety of palbociclib have not been studied in patients with critical visceral disease (see Pharmacology: Pharmacodynamics under Actions).
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 to use effective contraception during treatment with IBRANCE and for at least 3 weeks after the last dose.
Hepatic impairment: Administer IBRANCE with caution to patients with moderate or severe hepatic impairment, with close monitoring of signs of toxicity (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Renal impairment: Administer IBRANCE with caution to patients with moderate or severe renal impairment, with close monitoring of signs of toxicity (see Dosage & Administration and Pharmacology: Pharmacokinetics under Actions).
Concomitant treatment with inhibitors or inducers of CYP3A4: Strong inhibitors of CYP3A4 may lead to increased toxicity (see Interactions). Concomitant use of strong CYP3A inhibitors during treatment with palbociclib should be avoided. Coadministration should only be considered after careful evaluation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mg once daily. When the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see Interactions).
Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see Interactions).
Women of child bearing potential or their partners: Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see Use in Pregnancy & Lactation).
Lactose: This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.
Effects on ability to drive and use machines: IBRANCE has minor influence on the ability to drive and use machines. However, patients experiencing fatigue while taking IBRANCE should exercise caution when driving or operating machinery.
Use In Pregnancy & Lactation
Fertility: There were no effects on estrous cycle (female rats) or mating and fertility in rats in nonclinical studies. However, no clinical data have been obtained on fertility in human females. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib (see Pharmacology: Toxicology: Preclinical safety data under Actions). Men should consider sperm preservation prior to beginning therapy with IBRANCE.
Women of childbearing potential/pregnancy: There are no adequate and well-controlled studies using IBRANCE in pregnant women. Based on findings in animals and mechanism of action, palbociclib can cause fetal harm when administered to a pregnant woman. In animal studies, palbociclib was fetotoxic at maternally-toxic doses. IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception.
Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods during therapy and for at least 21 days or 97 days after completing therapy for females and males, respectively.
Lactation: No studies have been conducted in humans to assess the effect of IBRANCE on milk production, its presence in breast milk, or its effects on the breastfed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breastfeed.
Adverse Reactions
The following clinically significant adverse reactions are described as follows and elsewhere in the labeling: Neutropenia and ILD/Pneumonitis (see Precautions).
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.
Study 1: 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 Study 1 (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 Study 1. 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 Study 1.
Permanent discontinuation associated with an adverse reaction occurred in 43 of 444 (9.7%) patients receiving IBRANCE plus letrozole and in 13 of 222 (5.9%) 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 Study 1 are listed in Table 5. (See Table 5.)


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Additional adverse reactions occurring at an overall incidence of <10.0% of patients receiving IBRANCE plus letrozole in Study 1 included alanine aminotransferase increased (9.9%), aspartate aminotransferase increased (9.7%), epistaxis (9.2%), lacrimation increased (5.6%), dry eye (4.1%), vision blurred (3.6%), and febrile neutropenia (2.5%). (See Table 6.)


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Description of selected adverse reactions: Overall, neutropenia of any grade was reported in patients receiving IBRANCE regardless of the combination, with Grade 3 and Grade 4 neutropenia.
The median time to first episode of any grade neutropenia was 15 days (12-700 days) and the median duration of Grade >3 neutropenia was 7 days across 3 randomised clinical studies.
Febrile neutropenia has been reported in 2.1% of patients receiving palbociclib in combination with letrozole.
The most common adverse reactions (≥20%) of any grade reported in patients in the IBRANCE plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, nausea, fatigue, alopecia, stomatitis, anaemia and diarrhoea.
Dose reductions due to an adverse event of any grade occurred in 36.2% of patients receiving IBRANCE plus letrozole in PALOMA-1 and PALOMA-2. No dose reductions were allowed for the comparator arm. Permanent treatment discontinuation associated with an adverse event occurred in 10.6% patients receiving IBRANCE plus letrozole in PALOMA-1 and PALOMA-2 and in 5.0% of patients in the comparator arm.
In PALOMA-2 patients receiving IBRANCE plus letrozole, the starting dose of IBRANCE was 125 mg once daily. Dose reductions to 100 mg occurred in 36% of patients and dose reductions to 75 mg occurred in 14% of patients due to adverse events.
Neutropenia of any grade was reported in 78.9% of patients receiving IBRANCE plus letrozole in PALOMA-1 and PALOMA-2, with Grade 3 neutropenia reported in 55.2% of patients and Grade 4 neutropenia reported in 9.7% of patients (see Precautions). The most frequently reported Grade >3 adverse reactions (≥5%) in patients receiving IBRANCE plus letrozole by descending frequency were neutropenia, leukopenia, infections and anaemia.
The most frequently (≥ 1%) reported serious adverse drug reactions in patients receiving palbociclib plus letrozole (PALOMA-1 and PALOMA-2) were infections (4.6%) and febrile neutropenia (1.3%).
Cataract was reported in 3.2% of patients receiving IBRANCE plus letrozole and in 0.5% of patients receiving placebo plus letrozole in PALOMA-2.
Postmarketing Experience: The following adverse reactions have been identified during post-approval use of IBRANCE. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Respiratory disorders: Interstitial lung disease (ILD)/non-infectious pneumonitis.
Male patients with HR-positive, HER2-negative advanced or metastatic breast cancer: Based on limited data from postmarketing reports and electronic health records, the safety profile for men treated with IBRANCE is consistent with the safety profile in women treated with IBRANCE.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Palbociclib is primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time-dependent inhibitor of CYP3A.
Agents that may increase palbociclib plasma concentrations: Effect of CYP3A inhibitors: Data from a drug-drug interaction (DDI) study in healthy subjects indicate that coadministration of multiple 200 mg doses of itraconazole with a single 125 mg dose of IBRANCE increased palbociclib total exposure area under the plasma concentration-time curve from time zero to infinity (AUCinf) and the maximum observed plasma concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg dose of IBRANCE given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to: amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided.
Agents that may decrease palbociclib plasma concentrations: Effect of CYP3A inducers: Data from a DDI study in healthy subjects indicate that coadministration of multiple 600 mg doses of rifampin, a strong CYP3A inducer, with a single 125 mg dose of IBRANCE decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg dose of IBRANCE given alone. Data from a DDI study in healthy subjects indicate that coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg IBRANCE dose decreased palbociclib AUCinf and Cmax by 32% and 11%, respectively, relative to a single 125 mg dose of IBRANCE given alone.
The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentine, and St. John's wort, should be avoided.
Coadministration of a moderate CYP3A inducer (modafinil) decreased the plasma exposure of palbociclib in healthy subjects by 32%. Moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) can be used concurrently with IBRANCE when unavoidable. No dosing adjustments are required.
Effect of acid reducing agents: Data from a DDI study in healthy subjects indicated that coadministration of a single 125 mg dose of IBRANCE with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease) compared with a single 125 mg dose of IBRANCE administered alone.
Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists, or local antacids on palbociclib exposure.
Data from another DDI study in healthy subjects indicated that coadministration of a single dose of IBRANCE with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared with a single dose of IBRANCE administered alone.
Therefore, IBRANCE should be taken with food (see Dosage & Administration).
Effects of IBRANCE on other drugs: Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state in humans. In a DDI study in healthy subjects, coadministration of midazolam with multiple doses of palbociclib increased the midazolam AUCinf and Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.
Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61% in healthy subjects, 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 IBRANCE may increase its exposure.
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.
Letrozole: Data from a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 drugs were coadministered.
Fulvestrant: Data from a clinical study in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and fulvestrant when the 2 drugs were coadministered.
Goserelin: Data from a clinical study in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and goserelin when the 2 drugs were coadministered.
Tamoxifen: Data from a DDI study in healthy male subjects indicated that palbociclib exposures were comparable when a single dose of palbociclib was coadministered with multiple doses of tamoxifen and when palbociclib was given alone.
Drug-drug interaction between palbociclib and oral contraceptives: DDI studies of palbociclib with oral contraceptives have not been conducted (see Use in Pregnancy & Lactation).
In vitro studies with transporters: Based on in vitro data, palbociclib is predicted to inhibit intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib with medicinal products that are substrates of palbociclib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, rosuvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions.
Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCTI and then may increase the exposure of medical product substrates of this transporter (e.g., metformin).
Caution For Usage
Any unused product or waste material should be disposed in accordance with local requirements.
Storage
Store below 30°C.
Shelf life: 48 months.
MIMS Class
Targeted Cancer Therapy
ATC Classification
L01EF01 - palbociclib ; Belongs to the class of cyclin-dependent kinase (CDK) inhibitors. Used in the treatment of cancer.
Presentation/Packing
Hard cap 75 mg x 1 x 7's. 100 mg x 1 x 7's. 125 mg x 1 x 7's.
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