palbociclib: prescribing information – dosing, contraindications, interactions, side effects

IBRANCE is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer:
- in combination with an aromatase inhibitor;
- in combination with fulvestrant in women who have received prior endocrine therapy (see section 5.1).
In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.

Treatment with IBRANCE should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Posology
The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days. The treatment with IBRANCE should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.
When coadministered with palbociclib, the aromatase inhibitor should be administered according to the dose schedule reported in the Summary of Product Characteristics. Treatment of pre/perimenopausal women with the combination of palbociclib plus an aromatase inhibitor should always be combined with an LHRH agonist (see section 4.4).
When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the Summary of Product Characteristics of fulvestrant. Prior to the start of treatment with the combination of palbociclib plus fulvestrant, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.
Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.
Dose adjustments
Dose modification of IBRANCE is recommended based on individual safety and tolerability.
Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2, and 3 (see sections 4.4 and 4.8).
Table 1.
IBRANCE recommended dose modifications for adverse reactions
Dose level
Dose
Recommended 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 the treatment.
Complete blood count should be monitored prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.

For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of a cycle and as clinically indicated.
Absolute neutrophil counts (ANC) of ≥1,000/mm3 and platelet counts of ≥50,000/mm3 are recommended to receive IBRANCE.
Table 2.
IBRANCE dose modification and management – Haematological toxicities
CTCAE grade
Dose modifications
Grade 1 or 2
No dose adjustment is required.
Grade 3a
Day 1 of cycle:
Withhold IBRANCE, until recovery to Grade ≤2, and repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose.
Day 15 of first 2 cycles:
If Grade 3 on Day 15, continue IBRANCE at the current dose to complete cycle and repeat complete blood count on Day 22.
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below.
Consider dose reduction in cases of prolonged (> 1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles.
Grade 3 ANCb
(< 1,000 to 500/mm3)
+ Fever ≥38.5 ºC and/or infection
At any time:
Withhold IBRANCE until recovery to Grade ≤2
Resume at next lower dose.
Grade 4a
At any time:
Withhold IBRANCE until recovery to Grade ≤2.
Resume at next lower dose.
Grading according to CTCAE 4.0.
ANC=absolute neutrophil counts; CTCAE=Common Terminology Criteria for Adverse Events;
LLN=lower limit of normal.
a
Table applies to all haematological adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
b
ANC: Grade 1: ANC < LLN – 1,500/mm3; Grade 2: ANC 1,000 - < 1,500/mm3;
Grade 3: ANC 500 - < 1,000/mm3; Grade 4: ANC < 500/mm3.
Table 3.
IBRANCE dose modification and management – Non-haematological toxicities
CTCAE grade
Dose modifications
Grade 1 or 2
No dose adjustment is required.
Grade ≥3 non-haematological toxicity (if persisting despite medical treatment)
Withhold until symptoms resolve to:

Grade ≤1;

Grade ≤2 (if not considered a safety risk for the patient)
Resume at the next lower dose.
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events.
IBRANCE should be permanently discontinued in patients with severe interstitial lung disease (ILD)/pneumonitis (see section 4.4).

Special populations
Elderly
No dose adjustment of IBRANCE is necessary in patients ≥65 years of age (see section 5.2).
Hepatic impairment
No dose adjustment of IBRANCE 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 sections 4.4 and 5.2).
Renal impairment
No dose adjustment of IBRANCE is required for patients with mild, moderate or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min). Insufficient data are available in patients requiring haemodialysis to provide any dose adjustment recommendation in this patient population (see sections 4.4 and 5.2).
Paediatric population
There is no relevant use of IBRANCE in the paediatric population for the treatment of breast carcinoma. The efficacy of IBRANCE in children and adolescents < 18 years of age has not been demonstrated. Currently available data are described in sections 4.8, 5.1, and 5.2.
Method of administration
IBRANCE is for oral use. It should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see section 4.5).
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.

Treatment with IBRANCE should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Posology
The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days. The treatment with IBRANCE should be continued as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.
When coadministered with palbociclib, the aromatase inhibitor should be administered according to the dose schedule reported in the Summary of Product Characteristics. Treatment of pre/perimenopausal women with the combination of palbociclib plus an aromatase inhibitor should always be combined with an LHRH agonist (see section 4.4).
When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administered intramuscularly on Days 1, 15, 29, and once monthly thereafter. Please refer to the Summary of Product Characteristics of fulvestrant. Prior to the start of treatment with the combination of palbociclib plus fulvestrant, and throughout its duration, pre/perimenopausal women should be treated with LHRH agonists according to local clinical practice.
Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time.
Dose adjustments
Dose modification of IBRANCE is recommended based on individual safety and tolerability.
Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2, and 3 (see sections 4.4 and 4.8).
Table 1.
IBRANCE recommended dose modifications for adverse reactions
Dose level
Dose
Recommended 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 the treatment.
Complete blood count should be monitored prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 15 of the first 2 cycles, and as clinically indicated.
For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of a cycle and as clinically indicated.
Absolute neutrophil counts (ANC) of ≥1,000/mm3 and platelet counts of ≥50,000/mm3 are recommended to receive IBRANCE.

Table 2.
IBRANCE dose modification and management – Haematological toxicities
CTCAE grade
Dose modifications
Grade 1 or 2
No dose adjustment is required.
Grade 3a
Day 1 of cycle:
Withhold IBRANCE, until recovery to Grade ≤2, and repeat complete blood count monitoring within 1 week. When recovered to Grade ≤2, start the next cycle at the same dose.
Day 15 of first 2 cycles:
If Grade 3 on Day 15, continue IBRANCE at the current dose to complete cycle and repeat complete blood count on Day 22.
If Grade 4 on Day 22, see Grade 4 dose modification guidelines below.
Consider dose reduction in cases of prolonged (> 1 week) recovery from Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1 of subsequent cycles.
Grade 3 ANCb
(< 1,000 to 500/mm3)
+ Fever ≥38.5 ºC and/or infection
At any time:
Withhold IBRANCE until recovery to Grade ≤2
Resume at next lower dose.
Grade 4a
At any time:
Withhold IBRANCE until recovery to Grade ≤2.
Resume at next lower dose.
Grading according to CTCAE 4.0.
ANC=absolute neutrophil counts; CTCAE=Common Terminology Criteria for Adverse Events;
LLN=lower limit of normal.
a
Table applies to all haematological adverse reactions except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).
b
ANC: Grade 1: ANC < LLN – 1,500/mm3; Grade 2: ANC 1,000 - < 1,500/mm3;
Grade 3: ANC 500 - < 1,000/mm3; Grade 4: ANC < 500/mm3.
Table 3.
IBRANCE dose modification and management – Non-haematological toxicities
CTCAE grade
Dose modifications
Grade 1 or 2
No dose adjustment is required.
Grade ≥3 non-haematological toxicity (if persisting despite medical treatment)
Withhold until symptoms resolve to:

Grade ≤1;

Grade ≤2 (if not considered a safety risk for the patient)
Resume at the next lower dose.
Grading according to CTCAE 4.0.
CTCAE=Common Terminology Criteria for Adverse Events.
IBRANCE should be permanently discontinued in patients with severe interstitial lung disease (ILD)/pneumonitis (see section 4.4).
Special populations
Elderly
No dose adjustment of IBRANCE is necessary in patients ≥65 years of age (see section 5.2).
Hepatic impairment
No dose adjustment of IBRANCE 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 sections 4.4 and 5.2).

Renal impairment
No dose adjustment of IBRANCE is required for patients with mild, moderate or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min). Insufficient data are available in patients requiring haemodialysis to provide any dose adjustment recommendation in this patient population (see sections 4.4 and 5.2).
Paediatric population
There is no relevant use of IBRANCE in the paediatric population for the treatment of breast carcinoma. The efficacy of IBRANCE in children and adolescents < 18 years of age has not been demonstrated. Currently available data are described in sections 4.8, 5.1, and 5.2.
Method of administration
IBRANCE is for oral use. The tablets may be taken with or without food (see section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see section 4.5).
IBRANCE tablets should be swallowed whole (should not be chewed, crushed, or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Use of preparations containing St. John’s Wort (see section 4.5).

Summary of the safety profile
The overall safety profile of IBRANCE is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N=527 in combination with letrozole and N=345 in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer.
The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse

reactions of palbociclib were neutropenia, leukopenia, infections, anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase (ALT) increased.
Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination.
Permanent discontinuation due to an adverse reaction occurred in 5.2% of patients receiving IBRANCE in randomised clinical studies regardless of the combination.
Tabulated list of adverse reactions
Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The median duration of palbociclib treatment across the pooled dataset at the time of the final overall survival (OS) analysis was 14.8 months.
Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomised studies.
The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to < 1/10), and uncommon (≥1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 4.
Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System organ class Frequency Preferred terma (PT) All Grades n (%) Grade 3 n (%) Grade 4 n (%) Infections and infestations Very common Infectionsb 516 (59.2) 49 (5.6) 8 (0.9) Blood and lymphatic system disorders Very common Neutropeniac 716 (82.1) 500 (57.3) 97 (11.1) Leukopeniad 424 (48.6) 254 (29.1) 7 (0.8) Anaemiae 258 (29.6) 45 (5.2) 2 (0.2) Thrombocytopeniaf 194 (22.2) 16 (1.8) 4 (0.5) Common Febrile neutropenia 12 (1.4) 10 (1.1) 2 (0.2) Metabolism and nutrition disorders Very common Decreased appetite 152 (17.4) 8 (0.9) 0 (0.0) Nervous system disorders Common Dysgeusia 79 (9.1) 0 (0.0) 0 (0.0) Eye disorders Common Vision blurred 48 (5.5) 1 (0.1) 0 (0.0) Lacrimation increased 59 (6.8) 0 (0.0) 0 (0.0) Dry eye 36 (4.1) 0 (0.0) 0 (0.0) Vascular disorders Common Venous thromboembolismj 28 (3.2) 11 (1.3) 7 (0.8) Respiratory, thoracic and mediastinal disorders Common Epistaxis ILD/pneumonitisi 77 (8.8) 12 (1.4) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0)

Table 4.
Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System organ class Frequency Preferred terma (PT) All Grades n (%) Grade 3 n (%) Grade 4 n (%) Gastrointestinal disorders Very common Stomatitisg 264 (30.3) 8 (0.9) 0 (0.0) Nausea 314 (36.0) 5 (0.6) 0 (0.0) Diarrhoea 238 (27.3) 9 (1.0) 0 (0.0) Vomiting 165 (18.9) 6 (0.7) 0 (0.0) Skin and subcutaneous tissue disorders Very common Rashh 158 (18.1) 7 (0.8) 0 (0.0) Alopecia 234 (26.8) N/A N/A Dry skin 93 (10.7) 0 (0.0) 0 (0.0) Common Palmar-plantar erythrodysaesthesia syndrome 16 (1.8) 0 (0.0) 0 (0.0) Uncommon Cutaneous lupus erythematosus Erythema multiforme 1 (0.1) 1 (0.1) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) General disorders and administration site conditions Very common Fatigue 362 (41.5) 23 (2.6) 2 (0.2) Asthenia 118 (13.5) 14 (1.6) 1 (0.1) Pyrexia 115 (13.2) 1 (0.1) 0 (0.0) Investigations Very common ALT increased 92 (10.6) 18 (2.1) 1 (0.1) AST Increased 99 (11.4) 25 (2.9) 0 (0.0) Common Blood creatinine increased 57 (6.5) 3 (0.3) 2 (0.2) ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease;
N/n=number of patients; N/A=not applicable.
a
PTs are listed according to MedDRA 17.1.
b
Infections includes all PTs that are part of the System Organ Class Infections and infestations.
c
Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.
d
Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.
e
Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.
f
Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.
g
Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.
h
Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.
i
ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial Lung Disease (narrow).
j
Venous thromboembolism includes the following PTs: pulmonary embolism, embolism, deep vein thrombosis, peripheral embolism, thrombosis.
Table 5.
Laboratory abnormalities observed in pooled dataset from 3 randomised studies
(N=872)
IBRANCE plus letrozole or fulvestrant
Comparator arms*
Laboratory abnormalities
All grades
%
Grade 3
%
Grade 4
%
All grades
%
Grade 3
%
Grade 4
%
WBC decreased

Summary of the safety profile
The overall safety profile of IBRANCE is based on pooled data from 872 patients who received palbociclib in combination with endocrine therapy (N=527 in combination with letrozole and N=345 in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negative advanced or metastatic breast cancer.
The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, infections, anaemia, aspartate aminotransferase (AST) increased, fatigue, and alanine aminotransferase (ALT) increased.
Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination.
Permanent discontinuation due to an adverse reaction occurred in 5.2% of patients receiving IBRANCE in randomised clinical studies regardless of the combination.
Tabulated list of adverse reactions
Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The median duration of palbociclib treatment across the pooled dataset at the time of the final OS analysis was 14.8 months.
Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomised studies.
The adverse reactions are listed by system organ class and frequency category. Frequency categories are defined as: very common (≥1/10), common (≥1/100 to < 1/10), and uncommon (≥1/1,000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 4.
Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System Organ Class Frequency Preferred terma (PT) All Grades n (%) Grade 3 n (%) Grade 4 n (%) Infections and infestations

Table 4.
Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System Organ Class Frequency Preferred terma (PT) All Grades n (%) Grade 3 n (%) Grade 4 n (%) Very common Infectionsb 516 (59.2) 49 (5.6) 8 (0.9) Blood and lymphatic system disorders Very common Neutropeniac 716 (82.1) 500 (57.3) 97 (11.1) Leukopeniad 424 (48.6) 254 (29.1) 7 (0.8) Anaemiae 258 (29.6) 45 (5.2) 2 (0.2) Thrombocytopeniaf 194 (22.2) 16 (1.8) 4 (0.5) Common Febrile neutropenia 12 (1.4) 10 (1.1) 2 (0.2) Metabolism and nutrition disorders Very common Decreased appetite 152 (17.4) 8 (0.9) 0 (0.0) Nervous system disorders Common Dysgeusia 79 (9.1) 0 (0.0) 0 (0.0) Eye disorders Common Vision blurred 48 (5.5) 1 (0.1) 0 (0.0) Lacrimation increased 59 (6.8) 0 (0.0) 0 (0.0) Dry eye 36 (4.1) 0 (0.0) 0 (0.0) Vascular disorders Common Venous thromboembolismj 28 (3.2) 11 (1.3) 7 (0.8) Respiratory, thoracic and mediastinal disorders Common Epistaxis ILD/pneumonitisi 77 (8.8) 12 (1.4) 0 (0.0) 1 (0.1) 0 (0.0) 0 (0.0) Gastrointestinal disorders Very common Stomatitisg 264 (30.3) 8 (0.9) 0 (0.0) Nausea 314 (36.0) 5 (0.6) 0 (0.0) Diarrhoea 238 (27.3) 9 (1.0) 0 (0.0) Vomiting 165 (18.9) 6 (0.7) 0 (0.0) Skin and subcutaneous tissue disorders Very common Rashh 158 (18.1) 7 (0.8) 0 (0.0) Alopecia 234 (26.8) N/A N/A Dry skin 93 (10.7) 0 (0.0) 0 (0.0) Common Palmar-plantar erythrodysaesthesia syndrome 16 (1.8) 0 (0.0) 0 (0.0) Uncommon Cutaneous lupus erythematosus 1 (0.1) 0 (0.0) 0 (0.0) Erythema multiforme 1 (0.1) 0 (0.0) 0 (0.0) General disorders and administration site conditions Very common Fatigue 362 (41.5) 23 (2.6) 2 (0.2) Asthenia 118 (13.5) 14 (1.6) 1 (0.1) Pyrexia 115 (13.2) 1 (0.1) 0 (0.0) Investigations Very common ALT increased 92 (10.6) 18 (2.1) 1 (0.1) AST Increased 99 (11.4) 25 (2.9) 0 (0.0) Common Blood creatinine increased 57 (6.5) 3 (0.3) 2 (0.2) ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; N/n=number of patients; N/A=not applicable.

Table 4.
Adverse reactions based on pooled dataset from 3 randomised studies (N=872) and during post-marketing experience System Organ Class Frequency Preferred terma (PT) All Grades n (%) Grade 3 n (%) Grade 4 n (%) a PTs are listed according to MedDRA 17.1.
b
Infections includes all PTs that are part of the System Organ Class Infections and infestations.
c
Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.
d
Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.
e
Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.
f
Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.
g
Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.
h
Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.
i
ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial Lung Disease (narrow).
j
Venous thromboembolism includes the following PTs: pulmonary embolism, embolism, deep vein thrombosis, peripheral embolism, thrombosis.
Table 5.
Laboratory abnormalities observed in pooled dataset from 3 randomised studies
(N=872)
IBRANCE plus letrozole or fulvestrant
Comparator arms*
Laboratory abnormalities
All grades
%
Grade 3
%
Grade 4
%
All grades
%
Grade 3
%
Grade 4
%
WBC decreased

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 section 5.1).
Haematological disorders
Dose 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 sections 4.2 and 4.8).

Interstitial lung disease/pneumonitis
Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy.
Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 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, with fatalities reported (see section 4.8).
Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, IBRANCE should be immediately interrupted and the patient should be evaluated. IBRANCE should be permanently discontinued in patients with severe ILD or pneumonitis (see section 4.2).
Infections
Since IBRANCE has myelosuppressive properties, it may predispose patients to infections.
Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see section 4.8).
Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2).
Physicians should inform patients to promptly report any episodes of fever.
Venous thromboembolism
Venous thromboembolic events were reported in patients treated with IBRANCE (see section 4.8).
Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism, and treated as medically appropriate.
Hepatic impairment
IBRANCE should be administered with caution to patients with moderate or severe hepatic impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).
Renal impairment
IBRANCE should be administered with caution to patients with moderate or severe renal impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).
Concomitant treatment with inhibitors or inducers of CYP3A4
Strong inhibitors of CYP3A4 may lead to increased toxicity (see section 4.5). 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, the dose of IBRANCE should be increased (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see section 4.5).

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 section 4.5).
Women of childbearing potential or their partners
Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see section 4.6).
Lactose
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Sodium
This medicinal product contains less than 1 mmol (23 mg) sodium per capsule, that is to say essentially ‘sodium-free’.

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 section 5.1).
Haematological disorders
Dose 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 sections 4.2 and 4.8).
Interstitial lung disease/pneumonitis
Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with IBRANCE when taken in combination with endocrine therapy.
Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 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, with fatalities reported (see section 4.8).
Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to

have developed ILD/pneumonitis, IBRANCE should be immediately interrupted and the patient should be evaluated. IBRANCE should be permanently discontinued in patients with severe ILD or pneumonitis (see section 4.2).
Infections
Since IBRANCE has myelosuppressive properties, it may predispose patients to infections.
Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see section 4.8).
Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see section 4.2).
Physicians should inform patients to promptly report any episodes of fever.
Venous thromboembolism
Venous thromboembolic events were reported in patients treated with IBRANCE (see section 4.8).
Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism, and treated as medically appropriate.
Hepatic impairment
IBRANCE should be administered with caution to patients with moderate or severe hepatic impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).
Renal impairment
IBRANCE should be administered with caution to patients with moderate or severe renal impairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).
Concomitant treatment with inhibitors or inducers of CYP3A4
Strong inhibitors of CYP3A4 may lead to increased toxicity (see section 4.5). 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, the dose of IBRANCE should be increased (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see section 4.5).
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 section 4.5).
Women of childbearing potential or their partners
Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see section 4.6).

Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1.
In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A.
Effects of other medicinal products on the pharmacokinetics of palbociclib
Effect of CYP3A inhibitors
Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUCinf) and the peak concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone.
The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4).
No dose adjustments are needed for mild and moderate CYP3A inhibitors.
Effect of CYP3A inducers
Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg palbociclib dose given alone.
The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see sections 4.3 and 4.4).
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 IBRANCE dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4).
Effect of acid reducing agents
Under fed conditions (intake of a moderate-fat meal), coadministration of multiple doses of the proton pump inhibitor (PPI) rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib Cmax

by 41%, but had limited impact on AUCinf (13% decrease) compared with a single dose of 125 mg IBRANCE administered alone.
Under fasting conditions, the coadministration of multiple doses of the PPI rabeprazole with a single dose of 125 mg IBRANCE decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively.
Therefore, IBRANCE should be taken with food, preferably a meal (see sections 4.2 and 5.2).
Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, no clinically relevant effect of H2-receptor antagonists or local antacids on palbociclib exposure is expected when palbociclib is taken with food.
Effects of palbociclib on the pharmacokinetics of other medicinal products
Palbociclib is a weak, time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state. Coadministration of multiple doses of palbociclib with midazolam increased the midazolam AUCinf and Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.
The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE as IBRANCE may increase their exposure.
Drug-drug interaction between palbociclib and letrozole
Data from the drug-drug interaction (DDI) evaluation portion of a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 medicinal products were coadministered.
Effect of tamoxifen on palbociclib exposure
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 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 two medicinal products were coadministered.
Drug-drug interaction between palbociclib and oral contraceptives
DDI studies of palbociclib with oral contraceptives have not been conducted (see section 4.6).
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 P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, rosuvastatin, fluvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions. Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic

transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin).
Drug-drug interaction between palbociclib and statins
Concomitant use of palbociclib with statins which are substrates of CYP3A4 and/or BCRP may increase the risk of rhabdomyolysis due to increased statin plasma concentration. Cases of rhabdomyolysis including fatal cases have been reported following coadministration of palbociclib with simvastatin or atorvastatin.

Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1.
In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A.
Effects of other medicinal products on the pharmacokinetics of palbociclib
Effect of CYP3A inhibitors
Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib dose increased palbociclib total exposure (AUCinf) and the peak concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg palbociclib dose given alone.
The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4).
No dose adjustments are needed for mild and moderate CYP3A inhibitors.
Effect of CYP3A inducers
Coadministration of multiple 600 mg doses of rifampin with a single 125 mg palbociclib dose decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg palbociclib dose given alone.
The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see sections 4.3 and 4.4).
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 IBRANCE dose given alone. No dose adjustments are required for moderate CYP3A inducers (see section 4.4).
Effect of acid reducing agents
Coadministration of multiple doses of the PPI rabeprazole with a single 125 mg IBRANCE tablet under fasted conditions had no effect on the rate and extent of absorption of palbociclib when compared to a single 125 mg IBRANCE tablet administered alone.
Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs, no clinically relevant effect of H2-receptor antagonists or local antacids on palbociclib exposure is expected.
Effects of palbociclib on the pharmacokinetics of other medicinal products
Palbociclib is a weak, time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state. Coadministration of multiple doses of palbociclib with midazolam increased the midazolam AUCinf and Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.
The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE as IBRANCE may increase their exposure.

Drug-drug interaction between palbociclib and letrozole
Data from the drug-drug interaction (DDI) evaluation portion of a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 medicinal products were coadministered.
Effect of tamoxifen on palbociclib exposure
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 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 two medicinal products were coadministered.
Drug-drug interaction between palbociclib and oral contraceptives
DDI studies of palbociclib with oral contraceptives have not been conducted (see section 4.6).
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 P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g., pravastatin, rosuvastatin, fluvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions. Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin).
Drug-drug interaction between palbociclib and statins
Concomitant use of palbociclib with statins which are substrates of CYP3A4 and/or BCRP may increase the risk of rhabdomyolysis due to increased statin plasma concentration. Cases of rhabdomyolysis including fatal cases have been reported following coadministration of palbociclib with simvastatin or atorvastatin.

Women of childbearing potential/Contraception in males and females
Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see section 4.5).
Pregnancy
There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding
No studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breast-feed.
Fertility
There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans.
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 section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE.

Women of childbearing potential/Contraception in males and females
Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see section 4.5).
Pregnancy
There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception.
Breast-feeding

No studies have been conducted in humans or animals to assess the effect of palbociclib on milk production, its presence in breast milk, or its effects on the breast-fed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving palbociclib should not breast-feed.
Fertility
There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) in non-clinical reproductive studies. However, no clinical data have been obtained on fertility in humans.
Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in non-clinical safety studies, male fertility may be compromised by treatment with palbociclib (see section 5.3).
Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE.

IBRANCE has minor influence on the ability to drive and use machines. However, IBRANCE may cause fatigue and patients should exercise caution when driving or using machines.

In the event of a palbociclib overdose, both gastrointestinal (e.g., nausea, vomiting) and haematological (e.g., neutropenia) toxicity may occur and general supportive care should be provided.
5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EF01.
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 signalling 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 activity against luminal breast cancers, particularly ER-positive breast cancers. In the cell lines tested, the loss of retinoblastoma (Rb) was associated with loss of palbociclib activity. However, in a follow-up study with fresh tumour samples, no relation between RB1 expression and tumour response was observed. Similarly, no relation was observed when studying the response to palbociclib in in vivo models with patient-derived xenografts (PDX models). Available clinical data are reported in the clinical efficacy and safety section (see section 5.1).
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 efficacy and safety
Randomised Phase 3 Study PALOMA-2: IBRANCE in combination with letrozole
The efficacy of palbociclib in combination with letrozole versus letrozole plus placebo was evaluated in an international, randomised, double-blind, placebo-controlled, parallel-group, multicentre study conducted in women with ER-positive, HER2-negative locally advanced breast cancer not amenable to resection or radiation therapy with curative intent or metastatic breast cancer who had not received prior systemic treatment for their advanced disease.
A total of 666 postmenopausal women were randomised 2:1 to the palbociclib plus letrozole arm or placebo plus letrozole arm and were stratified by site of disease (visceral versus nonvisceral), disease-free interval from the end of (neo)adjuvant treatment to disease recurrence (de novo metastatic versus 12 months versus > 12 months), and by the type of prior (neo)adjuvant anticancer therapies (prior hormonal therapy versus 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.

The pharmacokinetics of palbociclib were characterised in patients with solid tumours including advanced breast cancer and in healthy volunteers.
Absorption
The mean Cmax of palbociclib is generally observed 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 area under the curve (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.
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 (see section 4.2).
Distribution
Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence. 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. In vitro, the uptake of palbociclib into human hepatocytes occurred mainly via passive diffusion. Palbociclib is not a substrate of OATP1B1 or OATP1B3.

The pharmacokinetics of palbociclib were characterised in patients with solid tumours including advanced breast cancer and in healthy volunteers.
Absorption
The Cmax of palbociclib is generally observed between 4 to 12 hours (time to reach maximum concentration [Tmax]) following oral administration of IBRANCE tablets. 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 area under the curve (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
The AUCinf and Cmax of palbociclib increased by 22% and 26%, respectively, when IBRANCE tablets were given with a high-fat, high-calorie meal (approximately 800 to 1,000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), and by 9% and 10%, respectively, when IBRANCE tablets were given with a moderate fat, standard-calorie meal (approximately 500 to 700 calories with 75 to 105, 250 to 350, and 175 to 245 calories from protein, carbohydrate, and fat, respectively), compared to IBRANCE tablets given under overnight fasted conditions. Based on these results, palbociclib tablets may be taken with or without food.
Distribution
Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence. 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. In vitro, the uptake of palbociclib into human hepatocytes occurred mainly via passive diffusion. Palbociclib is not a substrate of OATP1B1 or OATP1B3.
Biotransformation