Ibrance
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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 



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This medicinal product is subject to additional monitoring. This will allow quick identification of 
new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg hard capsules 
IBRANCE 100 mg hard capsules 
IBRANCE 125 mg hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
IBRANCE 75 mg hard capsules 
Each hard capsule contains 75 mg of palbociclib. 
 
Excipients with known effect 
Each hard capsule contains 56 mg of lactose (as monohydrate). 
 
IBRANCE 100 mg hard capsules 
Each hard capsule contains 100 mg of palbociclib. 
 
Excipients with known effect 
Each hard capsule contains 74 mg of lactose (as monohydrate). 
 
IBRANCE 125 mg hard capsules 
Each hard capsule contains 125 mg of palbociclib. 
 
Excipients with known effect 
Each hard capsule contains 93 mg of lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Hard capsule. 
 
IBRANCE 75 mg hard capsules 
Opaque, hard capsule, with a light orange body (printed “PBC 75” in white) and a light orange cap 
(printed “Pfizer” in white). The capsule length is 18.0 ± 0.3 mm. 
 
IBRANCE 100 mg hard capsules 
Opaque, hard capsule, with a light orange body (printed “PBC 100” in white) and a caramel cap 
(printed “Pfizer” in white). The capsule length is 19.4 ± 0.3 mm. 
 
IBRANCE 125 mg hard capsules 
Opaque, hard capsule, with a caramel body (printed “PBC 125” in white) and a caramel cap (printed 
“Pfizer” in white). The capsule length is 21.7 ± 0.3 mm. 
 
 



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4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
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. 
 



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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. 
 
Permanently discontinue IBRANCE 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). 



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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 
The safety and efficacy of IBRANCE in children and adolescents < 18 years of age have not been 
established. No data are available. 
 
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. 
 
4.3 Contraindications 
 
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). 
 
4.4 Special warnings and precautions for use 
 
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. 



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Across clinical trials (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). 
 
Monitor patients 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, interrupt IBRANCE immediately and evaluate the patient. Permanently 
discontinue IBRANCE 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 4.5% and 0.7% 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. 
 
Hepatic impairment 
 
Administer IBRANCE 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 
 
Administer IBRANCE 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, 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 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). 
 



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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. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 proton pump inhibitor (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. 
 



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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, 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). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception 
 
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). 
 



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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. 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 
4.8 Undesirable effects 
 
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 



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< 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) 
System organ class 
 Frequency 
   Preferred terma 

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) 

Respiratory, thoracic and mediastinal disorders 
Common 

   

Epistaxis 
ILD/pneumonitis*,i 

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) 

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) 

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; 
N/n=number of patients; N/A=not applicable.   
* Adverse Drug Reaction (ADR) identified post-marketing. 
a Preferred Terms (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. 



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Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872) 
System organ class 
 Frequency 
   Preferred terma 

All Grades 
n (%) 

Grade 3 
n (%) 

Grade 4 
n (%) 

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). 

 
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 97.4 41.8 1.0 26.2 0.2 0.2 
Neutrophils decreased 95.6 57.5 11.7 17.0 0.9 0.6 
Anaemia 80.1 5.6 N/A 42.1 2.3 N/A 
Platelets decreased 65.2 1.8 0.5 13.2 0.2 0.0 
AST increased 55.5 3.9 0.0 43.3 2.1 0.0 
ALT increased 46.1 2.5 0.1 33.2 0.4 0.0 
WBC-white blood cells; AST-aspartate aminotransferase; ALT-alanine aminotransferase; N-number of patients; 
N/A-not applicable. 
Note: Laboratory results are graded according to the NCI CTCAE version 4.0 severity grade. 
* letrozole or fulvestrant 
 
Description of selected adverse reactions 
 
Overall, neutropenia of any grade was reported in 716 (82.1%) patients receiving IBRANCE 
regardless of the combination, with Grade 3 neutropenia being reported in 500 (57.3%) patients, and 
Grade 4 neutropenia being reported in 97 (11.1 %) patients (see Table 4). 
 
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 0.9% of patients receiving IBRANCE in combination with 
fulvestrant and in 1.7% of patients receiving palbociclib in combination with letrozole. 
 
Febrile neutropenia has been reported in about 2% of patients exposed to IBRANCE across the overall 
clinical programme.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation 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 
listed in Appendix V. 
 
4.9 Overdose 
 
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. 
 
 



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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE33. 
 
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.  
 
Patients continued to receive 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 prognostic 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 



13 

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. 
The majority of patients (97.4%) had metastatic disease at baseline, 23.6% of patients had bone-only 
disease, and 49.2% of patients had visceral disease. 
 
The primary endpoint of the study was progression-free survival (PFS) evaluated according to 
Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, as assessed by investigator. 
Secondary efficacy endpoints included objective response (OR), clinical benefit response (CBR), 
safety, and change in quality of life (QoL).  
 
At the data cutoff date of 26-February-2016, the study met its primary objective of improving PFS. 
The observed hazard ratio (HR) was 0.576 (95% confidence interval [CI]: 0.46, 0.72) in favour of 
palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of < 0.000001. An updated 
analysis of the primary and secondary endpoints was performed after an additional 15 months of 
follow up (data cutoff date: 31-May-2017). A total of 405 PFS events were observed; 245 events 
(55.2%) in the palbociclib plus letrozole arm and 160 (72.1%) in the comparator arm respectively. 
 
Table 6 shows the efficacy results based on the primary and the updated analyses from the 
PALOMA-2 study, as assessed by the investigator and by the independent review.  
 

Table 6. PALOMA-2 (intent-to-treat population) - Efficacy results based on primary and 
updated cutoff dates 
 Primary analysis 

(26 February 2016 cutoff) 
Updated analysis 

(31 May 2017 cutoff) 
 IBRANCE 

plus letrozole 
(N = 444) 

Placebo 
plus letrozole 

(N = 222) 

IBRANCE 
plus letrozole 

(N = 444) 

Placebo 
plus letrozole 

(N = 222) 
Progression-free survival by investigator sssessment
    Number of events (%) 194 (43.7) 137 (61.7) 245 (55.2) 160 (72.1)
 Median PFS [months 

(95% CI)] 
24.8 (22.1, NE) 14.5 (12.9, 17.1) 27.6 (22.4, 30.3) 14.5 (12.3, 17.1) 

 Hazard ratio [(95% CI) 
and p-value] 

0.576 (0.463, 0.718), p< 0.000001 0.563 (0.461, 0.687), p< 0.000001 

Progression-free survival by independent assessment
Number of events (%) 152 (34.2) 96 (43.2) 193 (43.5) 118 (53.2)
Median PFS [months 
(95% CI)]  

30.5 (27.4, NE) 19.3 (16.4, 30.6) 35.7 (27.7, 38.9) 19.5 (16.6, 26.6) 

Hazard ratio (95% CI) 
and 1-sided p-value 

0.653 (0.505, 0.844), p=0.000532 0.611 (0.485, 0.769), p=0.000012 

OR* [% (95% CI)] 46.4 (41.7, 51.2) 38.3 (31.9, 45.0) 47.5 (42.8, 52.3) 38.7(32.3, 45.5)
OR* measurable disease 
[% (95% CI)]  

60.7 (55.2, 65.9) 49.1 (41.4, 56.9) 62.4 (57.0, 67.6) 49.7 (42.0, 57.4) 

CBR* [% (95% CI)] 85.8 (82.2, 88.9) 71.2 (64.7, 77.0) 85.6 (82.0, 88.7)  71.2 (64.7, 77.0)
N=number of patients; CI=confidence interval; NE=not estimable; OR=objective response; CBR=clinical benefit 
response; PFS=progression-free survival.  
* Secondary endpoints results are based on confirmed and unconfirmed responses according to RECIST 1.1. 
 



14 

The Kaplan-Meier curves for PFS based on the updated cutoff date of 31 May 2017 are displayed in 
Figure 1 below. 
 
Figure 1. Kaplan-Meier plot of progression-free survival (investigator assessment, 

intent-to-treat population) – PALOMA-2 study (31-May-2017) 

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Pr
og

re
ss

io
n-

Fr
ee

 S
ur

vi
va

l P
ro

ba
bi

lit
y 

(%
)

palbociclib+letrozole
placebo+letrozole

444 394 359 327 294 262 239 221 204 192 164 146 83 26 5 2PAL+LET
222 170 147 129 114 97 80 73 61 55 45 37 26 5 2 2 2PCB+LET

Number of patients at risk

 
PAL=palbociclib; LET=letrozole; PCB=placebo. 
 
A series of prespecified subgroup PFS analyses was performed based on prognostic factors and 
baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the 
risk of disease progression or death in favour of 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 analysis.  
 
Based on the 31-May-2017 data cutoff date, this reduction in risk continued to be observed in the 
following subgroups: (1) patients with either visceral metastases (HR of 0.62 [95% CI: 0.47, 0.81], 
median progression-free survival [mPFS] 19.3 months versus 12.3 months) or without visceral 
metastases (HR of 0.50 [95% CI: 0.37, 0.67], mPFS 35.9 months versus 17.0 months) and (2) patients 
with either bone only disease (HR of 0.41 [95% CI: 0.26, 0.63], mPFS 36.2 months versus 
11.2 months) or without bone-only disease (HR of 0.62 [95% CI: 0.50, 0.78], mPFS 24.2 months 
versus 14.5 months). Similarly, a reduction in the risk of disease progression or death in the 
palbociclib plus letrozole arm was observed in 512 patients whose tumour tested positive for Rb 
protein expression by immunohistochemistry (IHC) (HR of 0.543 [95% CI: 0.433, 0.681], mPFS 
27.4 months versus 13.7 months). For the 51 patients IHC negative for Rb expression, the difference 
between treatment arms was not statistically significant (HR of 0.868 [95% CI: 0.424, 1.777], mPFS 
23.2 versus 18.5 months) for the palbociclib plus letrozole arm versus the placebo plus letrozole arm, 
respectively. 
 
Additional efficacy measures (OR and time to response [TTR]) assessed in the sub-groups of patients 
with or without visceral disease based on the 31-May-2017 updated cutoff date are displayed in 
Table 7. 
 



15 

Table 7. Efficacy results in patients with visceral or non-visceral disease from PALOMA–2 
study (intent-to-treat population; 31-May-2017 cutoff date)  

 Visceral disease Non-visceral disease 
 IBRANCE 

plus letrozole 
(N=214)

Placebo 
plus letrozole 

(N=110)

IBRANCE 
plus letrozole 

(N=230) 

Placebo 
plus letrozole 

(N=112)
OR [% (95% CI)]  59.8 

(52.9, 66.4) 
46.4 

(36.8, 56.1) 
36.1 

(29.9, 42.7) 
31.3 

(22.8, 40.7) 
TTR, Median [months 
(range)] 

5.4 
(2.0, 30.4) 

5.3 
(2.6, 27.9) 

3.0 
(2.1, 27.8) 

5.5 
(2.6, 22.2) 

N=number of patients; CI=confidence interval; OR=objective response based on confirmed and unconfirmed 
responses according to RECIST 1.1; TTR=time to first tumour response.
 
At the time of the updated analyses, the median time from randomisation to second subsequent therapy 
was 38.8 months in the palbociclib + letrozole arm and 28.8 months in the placebo + letrozole arm, 
HR 0.73 (95% CI: 0.58, 0.91). 
 
Randomised Phase 3 Study PALOMA-3: IBRANCE in combination with fulvestrant  
 
The efficacy of palbociclib in combination with fulvestrant versus fulvestrant plus placebo was 
evaluated in an international, randomised, double-blind, parallel-group, multicentre study conducted in 
women with HR-positive, HER2-negative locally advanced breast cancer not amenable to resection or 
radiation therapy with curative intent or metastatic breast cancer, regardless of their menopausal 
status, whose disease progressed after prior endocrine therapy in the (neo)adjuvant or metastatic 
setting. 
 
A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months from 
completion of adjuvant endocrine therapy or on or within 1 month from prior endocrine therapy for 
advanced disease, were randomised 2:1 to palbociclib plus fulvestrant or placebo plus fulvestrant and 
stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry 
(pre/peri- versus postmenopausal), and presence of visceral metastases. Pre/perimenopausal women 
received the LHRH agonist goserelin. Patients with advanced/metastatic, 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 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 prognostic characteristics between the 
palbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The median age of patients 
enrolled in this study was 57 years (range 29, 88). In each treatment arm the majority of patients were 
White, had documented sensitivity to prior hormonal therapy, and were postmenopausal. 
Approximately 20% of patients were pre/perimenopausal. All patients had received prior systemic 
therapy and most patients in each treatment arm had received a previous chemotherapy regimen for 
their primary diagnosis. More than half (62%) had an ECOG PS of 0, 60% had visceral metastases, 
and 60% had received more than 1 prior hormonal regimen for their primary diagnosis. 
 
The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST 1.1. 
Supportive PFS analyses were based on an Independent Central Radiology Review. Secondary 
endpoints included OR, CBR, overall survival (OS), safety, and time-to-deterioration (TTD) in pain 
endpoint.  
 
The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis 
conducted on 82% of the planned PFS events; the results crossed the prespecified Haybittle-Peto 



16 

efficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and a 
clinically meaningful treatment effect. A more mature update of efficacy data is reported in Table 8. 
 
After a median follow-up time of 45 months, the final OS analysis was performed based on 310 events 
(60% of randomised patients). A 6.9-month difference in median OS in the palbociclib plus fulvestrant 
arm compared with the placebo plus fulvestrant arm was observed; this result was not statistically 
significant at the prespecified significance level of 0.0235 (1-sided). In the placebo plus fulvestrant 
arm, 15.5% of randomised patients received palbociclib and other CDK inhibitors as post progression 
subsequent treatments. 
 
The results from the investigator-assessed PFS and final OS data from PALOMA-3 study are 
presented in Table 8. The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively. 
 
Table 8. Efficacy results – PALOMA-3 study (investigator assessment, intent-to-treat 

population) 
 Updated analysis 

(23 October 2015 cutoff) 
 IBRANCE 

plus fulvestrant 
(N=347) 

Placebo 
plus fulvestrant 

(N=174) 
Progression-free survival (PFS) 
    Number of events (%) 200 (57.6) 133 (76.4) 
 Median [months (95% CI)]  11.2 (9.5, 12.9) 4.6 (3.5, 5.6) 
 Hazard ratio (95% CI) and p-value 0.497 (0.398, 0.620), p< 0.000001 
Secondary efficacy endpoints  
OR [% (95% CI)] 26.2 (21.7, 31.2) 13.8 (9.0, 19.8)
OR (measurable disease) [% (95% CI)] 33.7 (28.1, 39.7) 17.4 (11.5, 24.8)
CBR [% (95% CI)] 68.0 (62.8, 72.9) 39.7 (32.3, 47.3)
Final overall survival (OS) 
(13 April 2018 cutoff) 
Number of events (%) 201 (57.9) 109 (62.6) 
Median [months (95% CI)] 34.9 (28.8, 40.0) 28.0 (23.6, 34.6) 
Hazard ratio (95% CI) and p-value† 0.814 (0.644, 1.029) 

p=0.0429†* 
CBR=clinical benefit response; CI=confidence interval; N=number of patients; OR=objective response.  
Secondary endpoint results are based on confirmed and unconfirmed responses according to RECIST 1.1. 
* Not statistically significant.  
† 1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior 
endocrine therapy per randomisation. 
 



17 

Figure 2. Kaplan-Meier plot of progression-free survival (investigator assessment, 
intent-to-treat population) – PALOMA-3 study (23 October 2015 cutoff) 

0 2 4 6 8 10 12 14 16 18 20 22
Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Pr
og

re
ss

io
n-

Fr
ee

 S
ur

vi
va

l P
ro

ba
bi

lit
y 

(%
)

palbociclib+fulvestrant
placebo+fulvestrant

347 276 245 215 189 168 137 69 38 12 2 1PAL+FUL
174 112 83 62 51 43 29 15 11 4 1PCB+FUL

Number of patients at risk

 
FUL=fulvestrant; PAL=palbociclib; PCB=placebo. 
 
A reduction in the risk of disease progression or death in the palbociclib plus fulvestrant arm was 
observed in all individual patient subgroups defined by stratification factors and baseline 
characteristics. This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 0.75]) 
and postmenopausal women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with visceral site of 
metastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of 
0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in the 
metastatic setting, whether 0 (HR of 0.59 [95% CI: 0.37, 0.93]), 1 (HR of 0.46 [95% CI: 0.32, 
0.64]), 2 (HR of 0.48 [95% CI: 0.30, 0.76]), or ≥ 3 lines (HR of 0.59 [95% CI: 0.28, 1.22]). 
 
Figure 3. Kaplan-Meier plot of overall survival (intent-to-treat population) – PALOMA-3 

study (13 April 2018 cutoff) 

0 6 12 18 24 30 36 42 48 54
Time (Month)

0

10

20

30

40

50

60

70

80

90

100

O
ve

ra
ll 

Su
rv

iv
al

 P
ro

ba
bi

lit
y 

(%
)

palbociclib+fulvestrant
placebo+fulvestrant

347 321 286 247 209 165 148 126 17PAL+FUL
174 155 135 115 86 68 57 43 7PCB+FUL

Number of patients at risk

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



18 

 
Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without 
visceral disease are displayed in Table 9. 
 
Table 9. Efficacy results in visceral and non-visceral disease from PALOMA–3 study 

(intent-to-treat population) 
 Visceral disease Non-visceral disease 
 IBRANCE 

plus 
fulvestrant 

(N=206) 

Placebo 
plus 

fulvestrant 
(N=105) 

IBRANCE 
plus 

fulvestrant 
(N=141) 

Placebo 
plus 

fulvestrant 
(N=69) 

OR [%, (95% CI)]  35.0 
(28.5, 41.9) 

13.3 
(7.5, 21.4) 

13.5 
(8.3, 20.2) 

14.5 
(7.2, 25.0) 

TTR, Median 
[months (range)] 

3.8 
(3.5, 16.7) 

5.4 
(3.5, 16.7) 

3.7 
(1.9, 13.7) 

3.6 
(3.4, 3.7) 

N=number of patients; CI=confidence interval; OR=objective response based on confirmed and unconfirmed 
responses according to RECIST 1.1; TTR=time to first tumour response.
 
Patient-reported symptoms were assessed using the European Organisation for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and its Breast Cancer Module 
(EORTC QLQ-BR23). A total of 335 patients in the palbociclib plus fulvestrant arm and 166 patients 
in the fulvestrant only arm completed the questionnaire at baseline and at least 1 postbaseline visit. 
 
Time-to-Deterioration was prespecified as time between baseline and first occurrence of ≥ 10 points 
increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a 
symptom benefit by significantly delaying time-to-deterioration in pain symptom compared with 
placebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; 
p< 0.001).   
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
IBRANCE in all subsets of the paediatric population in the treatment of breast carcinoma (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
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 



19 

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. 
 
Biotransformation 
 
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 sulphonation, with acylation 
and glucuronidation contributing as minor pathways. Palbociclib was the major circulating 
drug-derived entity in plasma.  
 
The majority of the material was excreted as metabolites. In faeces, 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 
sulphotransferase (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 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 92% of the total administered radioactive 
dose was recovered in 15 days; faeces (74% of dose) was the major route of excretion, with 17% of 
the dose recovered in urine. Excretion of unchanged palbociclib in faeces and urine was 2% and 7% of 
the administered dose, respectively. 
 
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. 
 
In vitro evaluations indicate that palbociclib has low potential to inhibit the activities of organic anion 
transporter (OAT)1, OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide 
(OATP)1B1, OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations.  
 
Special populations 
 
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 38 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. 
 
Paediatric population 
Pharmacokinetics of palbociclib has not been evaluated in patients < 18 years of age. 
 



20 

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 (Child-Pugh class C) hepatic impairment, 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 × ULN 
and any AST), mild hepatic impairment had no effect on the pharmacokinetics of palbociclib. 
 
Renal impairment 
Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total 
palbociclib exposure (AUCinf) 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 pharmacokinetics of 
palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring 
haemodialysis. 
 
Ethnicity 
In a pharmacokinetic study in healthy volunteers, palbociclib 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 Japanese or 
Asian breast cancer patients after multiple dosing. Based on an analysis of the cumulative 
pharmacokinetic, safety, and efficacy data across Asian and non-Asian populations, no dose 
adjustment based on Asian race is considered necessary. 
 
5.3 Preclinical safety data 
 
The primary target organ findings of potential relevance to humans included haematolymphopoietic 
and male reproductive organ effects in rats and dogs in studies up to 39 weeks duration. Effects on 
glucose metabolism were associated with findings in the pancreas and secondary effects on eye, teeth, 
kidney, and adipose tissue in studies ≥ 15 weeks duration in rats only and bone changes were observed 
in rats only following 27 weeks of dosing. These systemic toxicities were generally observed at 
clinically relevant exposures based on AUC. 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. The reversibility of the effects 
on glucose homeostasis, pancreas, eye, kidney, and bone was not established following a 12-week 
nondosing period, whereas partial to full reversal of effects on the haematolymphopoietic and male 
reproductive systems, teeth, and adipose tissue was observed. 
 
Carcinogenicity 
 
Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat 
study. Palbociclib was negative for carcinogenicity in transgenic mice at doses up to 60 mg/kg/day 
(No Observed Effect Level [NOEL] approximately 11 times human clinical exposure based on AUC). 
Palbociclib-related neoplastic finding in rats included an increased incidence of microglial cell 
tumours in the central nervous system of males at 30 mg/kg/day; there were no neoplastic findings in 
female rats at any dose up to 200 mg/kg/day. The NOEL for palbociclib-related carcinogenicity effects 
was 10 mg/kg/day (approximately 2 times the human clinical exposure based on AUC) and 



21 

200 mg/kg/day (approximately 4 times the human clinical exposure based on AUC) in males and 
females, respectively. 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 exposure of animals at 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 non-clinical 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, respectively. Partial reversibility of male reproductive organ 
effects was observed in the rat and dog following a 4- and 12-week nondosing 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 is a reversible inhibitor of cyclin-dependent kinases 4 and 6, which are both involved in 
regulating the cell cycle. It may therefore have risk of foetal harm if used during pregnancy. 
Palbociclib was foetotoxic 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 foetal 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 foetal exposure and 
cross-placenta transfer have not been examined.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
 
Microcrystalline cellulose 
Lactose monohydrate 
Sodium starch glycolate type A 
Colloidal anhydrous silica 
Magnesium stearate 
 



22 

Capsule shell  
 
Gelatin 
Red iron oxide (E172) 
Yellow iron oxide (E172) 
Titanium dioxide (E171) 
 
Printing ink 
 
Shellac 
Titanium dioxide (E171) 
Ammonium hydroxide (28% solution) 
Propylene glycol 
Simeticone 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
PVC/PCTFE/PVC/Al blister strip containing 7 hard capsules (one capsule per cell). Each carton 
contains 21 hard capsules (3 blister strips per pack) or 63 hard capsules (9 blister strips per pack). 
 
HDPE bottle with a PP closure containing 21 hard capsules. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
IBRANCE 75 mg hard capsules 
EU/1/16/1147/001 
EU/1/16/1147/002 
EU/1/16/1147/007 
 



23 

IBRANCE 100 mg hard capsules 
EU/1/16/1147/003 
EU/1/16/1147/004 
EU/1/16/1147/008 
 
IBRANCE 125 mg hard capsules 
EU/1/16/1147/005 
EU/1/16/1147/006 
EU/1/16/1147/009 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 09 November 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 



24 

 
This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 
See section 4.8 for how to report adverse reactions. 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg film-coated tablets 
IBRANCE 100 mg film-coated tablets 
IBRANCE 125 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
IBRANCE 75 mg film-coated tablets 
Each film-coated tablet contains 75 mg of palbociclib. 
 
IBRANCE 100 mg film-coated tablets 
Each film-coated tablet contains 100 mg of palbociclib. 
 
IBRANCE 125 mg film-coated tablets 
Each film-coated tablet contains 125 mg of palbociclib. 
 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet (tablet). 
 
IBRANCE 75 mg film-coated tablets 
Round, 10.3 mm, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC 75” 
on the other side. 
 
IBRANCE 100 mg film-coated tablets 
Oval, 15.0 x 8.0 mm, green, film-coated tablets debossed with “Pfizer” on one side and “PBC 100” on 
the other side. 
 
IBRANCE 125 mg film-coated tablets 
Oval, 16.2 x 8.6 mm, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC 
125” on the other side.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 



25 

4.2 Posology and method of administration 
 
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. 
 



26 

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. 
 
Permanently discontinue IBRANCE 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). 



27 

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 
The safety and efficacy of IBRANCE in children and adolescents < 18 years of age have not been 
established. No data are available. 
 
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. 
 
4.3 Contraindications 
 
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). 
 
4.4 Special warnings and precautions for use 
 
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 trials (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). 
 
Monitor patients 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 



28 

developed ILD/pneumonitis, interrupt IBRANCE immediately and evaluate the patient. Permanently 
discontinue IBRANCE 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 4.5% and 0.7% 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. 
 
Hepatic impairment 
 
Administer IBRANCE 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 
 
Administer IBRANCE 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, 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 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). 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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.  



29 

 
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 proton pump inhibitor (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. 
 



30 

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, 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). 
 
4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential/Contraception 
 
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. 
 
4.7 Effects on ability to drive and use machines 
 
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. 
 



31 

4.8 Undesirable effects 
 
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) 
System Organ Class 
 Frequency 
   Preferred terma 

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) 



32 

Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872) 
System Organ Class 
 Frequency 
   Preferred terma 

All Grades 
n (%) 

Grade 3 
n (%) 

Grade 4 
n (%) 

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) 

Respiratory, thoracic and mediastinal disorders 
Common 

   

Epistaxis 
ILD/pneumonitis*,i 

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) 

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) 

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; 
N/n=number of patients; N/A=not applicable.   
* Adverse Drug Reaction (ADR) identified post-marketing. 
a Preferred Terms (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). 

 



33 

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 97.4 41.8 1.0 26.2 0.2 0.2 
Neutrophils decreased 95.6 57.5 11.7 17.0 0.9 0.6 
Anaemia 80.1 5.6 N/A 42.1 2.3 N/A 
Platelets decreased 65.2 1.8 0.5 13.2 0.2 0.0 
AST increased 55.5 3.9 0.0 43.3 2.1 0.0 
ALT increased 46.1 2.5 0.1 33.2 0.4 0.0 
WBC-white blood cells; AST-aspartate aminotransferase; ALT-alanine aminotransferase; N-number of patients; 
N/A-not applicable. 
Note: Laboratory results are graded according to the NCI CTCAE version 4.0 severity grade. 
* letrozole or fulvestrant 
 
Description of selected adverse reactions 
 
Overall, neutropenia of any grade was reported in 716 (82.1%) patients receiving IBRANCE 
regardless of the combination, with Grade 3 neutropenia being reported in 500 (57.3%) patients, and 
Grade 4 neutropenia being reported in 97 (11.1 %) patients (see Table 4). 
 
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 0.9% of patients receiving IBRANCE in combination with 
fulvestrant and in 1.7% of patients receiving palbociclib in combination with letrozole. 
 
Febrile neutropenia has been reported in about 2% of patients exposed to IBRANCE across the overall 
clinical programme.  
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation 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 
listed in Appendix V. 
 
4.9 Overdose 
 
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 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01XE33. 
 
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. 
 



34 

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.  
 
Patients continued to receive 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 prognostic 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. 
The majority of patients (97.4%) had metastatic disease at baseline, 23.6% of patients had bone-only 
disease, and 49.2% of patients had visceral disease. 
 
The primary endpoint of the study was progression-free survival (PFS) evaluated according to 
Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, as assessed by investigator. 
Secondary efficacy endpoints included objective response (OR), clinical benefit response (CBR), 
safety, and change in quality of life (QoL).  
 
At the data cutoff date of 26-February-2016, the study met its primary objective of improving PFS. 
The observed hazard ratio (HR) was 0.576 (95% confidence interval [CI]: 0.46, 0.72) in favour of 



35 

palbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of < 0.000001. An updated 
analysis of the primary and secondary endpoints was performed after an additional 15 months of 
follow up (data cutoff date: 31-May-2017). A total of 405 PFS events were observed; 245 events 
(55.2%) in the palbociclib plus letrozole arm and 160 (72.1%) in the comparator arm respectively. 
 
Table 6 shows the efficacy results based on the primary and the updated analyses from the 
PALOMA-2 study, as assessed by the investigator and by the independent review.  
 

Table 6. PALOMA-2 (intent-to-treat population) - Efficacy results based on primary and 
updated cutoff dates 
 Primary analysis 

(26 February 2016 cutoff) 
Updated analysis 

(31 May 2017 cutoff) 
 IBRANCE 

plus letrozole 
(N = 444) 

Placebo 
plus letrozole 

(N = 222) 

IBRANCE 
plus letrozole 

(N = 444) 

Placebo 
plus letrozole 

(N = 222) 
Progression-free survival by investigator assessment
    Number of events (%) 194 (43.7) 137 (61.7) 245 (55.2) 160 (72.1)
 Median PFS [months 

(95% CI)] 
24.8 (22.1, NE) 14.5 (12.9, 17.1) 27.6 (22.4, 30.3) 14.5 (12.3, 17.1) 

 Hazard ratio [(95% CI) 
and p-value] 

0.576 (0.463, 0.718), p< 0.000001 0.563 (0.461, 0.687), p< 0.000001 

Progression-free survival by independent assessment
Number of events (%) 152 (34.2) 96 (43.2) 193 (43.5) 118 (53.2)
Median PFS [months 
(95% CI)]  

30.5 (27.4, NE) 19.3 (16.4, 30.6) 35.7 (27.7, 38.9) 19.5 (16.6, 26.6) 

Hazard ratio (95% CI) 
and 1-sided p-value 

0.653 (0.505, 0.844), p=0.000532 0.611 (0.485, 0.769), p=0.000012 

OR* [% (95% CI)] 46.4 (41.7, 51.2) 38.3 (31.9, 45.0) 47.5 (42.8, 52.3) 38.7(32.3, 45.5)
OR* measurable disease 
[% (95% CI)]  

60.7 (55.2, 65.9) 49.1 (41.4, 56.9) 62.4 (57.0, 67.6) 49.7 (42.0, 57.4) 

CBR* [% (95% CI)] 85.8 (82.2, 88.9) 71.2 (64.7, 77.0) 85.6 (82.0, 88.7)  71.2 (64.7, 77.0)
N=number of patients; CI=confidence interval; NE=not estimable; OR=objective response; CBR=clinical benefit 
response; PFS=progression-free survival.  
* Secondary endpoints results are based on confirmed and unconfirmed responses according to RECIST 1.1. 
 



36 

The Kaplan-Meier curves for PFS based on the updated cutoff date of 31 May 2017 are displayed in 
Figure 1 below. 
 
Figure 1. Kaplan-Meier plot of progression-free survival (investigator assessment, 

intent-to-treat population) – PALOMA-2 study (31-May-2017) 

0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Pr
og

re
ss

io
n-

Fr
ee

 S
ur

vi
va

l P
ro

ba
bi

lit
y 

(%
)

palbociclib+letrozole
placebo+letrozole

444 394 359 327 294 262 239 221 204 192 164 146 83 26 5 2PAL+LET
222 170 147 129 114 97 80 73 61 55 45 37 26 5 2 2 2PCB+LET

Number of patients at risk

 
PAL=palbociclib; LET=letrozole; PCB=placebo. 
 
A series of prespecified subgroup PFS analyses was performed based on prognostic factors and 
baseline characteristics to investigate the internal consistency of treatment effect. A reduction in the 
risk of disease progression or death in favour of 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 analysis.  
 
Based on the 31-May-2017 data cutoff date, this reduction in risk continued to be observed in the 
following subgroups: (1) patients with either visceral metastases (HR of 0.62 [95% CI: 0.47, 0.81], 
median progression-free survival [mPFS] 19.3 months versus 12.3 months) or without visceral 
metastases (HR of 0.50 [95% CI: 0.37, 0.67], mPFS 35.9 months versus 17.0 months) and (2) patients 
with either bone only disease (HR of 0.41 [95% CI: 0.26, 0.63], mPFS 36.2 months versus 
11.2 months) or without bone-only disease (HR of 0.62 [95% CI: 0.50, 0.78], mPFS 24.2 months 
versus 14.5 months). Similarly, a reduction in the risk of disease progression or death in the 
palbociclib plus letrozole arm was observed in 512 patients whose tumour tested positive for Rb 
protein expression by immunohistochemistry (IHC) (HR of 0.543 [95% CI: 0.433, 0.681], mPFS 
27.4 months versus 13.7 months). For the 51 patients IHC negative for Rb expression, the difference 
between treatment arms was not statistically significant (HR of 0.868 [95% CI: 0.424, 1.777], mPFS 
23.2 versus 18.5 months) for the palbociclib plus letrozole arm versus the placebo plus letrozole arm, 
respectively. 
 
Additional efficacy measures (OR and time to response [TTR]) assessed in the sub-groups of patients 
with or without visceral disease based on the 31-May-2017 updated cutoff date are displayed in 
Table 7. 
 



37 

Table 7. Efficacy results in patients with visceral or non-visceral disease from PALOMA–2 
study (intent-to-treat population; 31-May-2017 cutoff date)  

 Visceral disease Non-visceral disease 
 IBRANCE 

plus letrozole 
(N=214)

Placebo 
plus letrozole 

(N=110)

IBRANCE 
plus letrozole 

(N=230) 

Placebo 
plus letrozole 

(N=112)
OR [% (95% CI)]  59.8 

(52.9, 66.4) 
46.4 

(36.8, 56.1) 
36.1 

(29.9, 42.7) 
31.3 

(22.8, 40.7) 
TTR, Median [months 
(range)] 

5.4 
(2.0, 30.4) 

5.3 
(2.6, 27.9) 

3.0 
(2.1, 27.8) 

5.5 
(2.6, 22.2) 

N=number of patients; CI=confidence interval; OR=objective response based on confirmed and unconfirmed 
responses according to RECIST 1.1; TTR=time to first tumour response.
 
At the time of the updated analyses, the median time from randomisation to second subsequent therapy 
was 38.8 months in the palbociclib + letrozole arm and 28.8 months in the placebo + letrozole arm, 
HR 0.73 (95% CI: 0.58, 0.91). 
 
Randomised Phase 3 Study PALOMA-3: IBRANCE in combination with fulvestrant  
 
The efficacy of palbociclib in combination with fulvestrant versus fulvestrant plus placebo was 
evaluated in an international, randomised, double-blind, parallel-group, multicentre study conducted in 
women with HR-positive, HER2-negative locally advanced breast cancer not amenable to resection or 
radiation therapy with curative intent or metastatic breast cancer, regardless of their menopausal 
status, whose disease progressed after prior endocrine therapy in the (neo)adjuvant or metastatic 
setting. 
 
A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months from 
completion of adjuvant endocrine therapy or on or within 1 month from prior endocrine therapy for 
advanced disease, were randomised 2:1 to palbociclib plus fulvestrant or placebo plus fulvestrant and 
stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry 
(pre/peri- versus postmenopausal), and presence of visceral metastases. Pre/perimenopausal women 
received the LHRH agonist goserelin. Patients with advanced/metastatic, 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 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 prognostic characteristics between the 
palbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The median age of patients 
enrolled in this study was 57 years (range 29, 88). In each treatment arm the majority of patients were 
White, had documented sensitivity to prior hormonal therapy, and were postmenopausal. 
Approximately 20% of patients were pre/perimenopausal. All patients had received prior systemic 
therapy and most patients in each treatment arm had received a previous chemotherapy regimen for 
their primary diagnosis. More than half (62%) had an ECOG PS of 0, 60% had visceral metastases, 
and 60% had received more than 1 prior hormonal regimen for their primary diagnosis. 
 
The primary endpoint of the study was investigator-assessed PFS evaluated according to RECIST 1.1. 
Supportive PFS analyses were based on an Independent Central Radiology Review. Secondary 
endpoints included OR, CBR, overall survival (OS), safety, and time-to-deterioration (TTD) in pain 
endpoint.  
 
The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysis 
conducted on 82% of the planned PFS events; the results crossed the prespecified Haybittle-Peto 



38 

efficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and a 
clinically meaningful treatment effect.  
 
A more mature update of efficacy data is reported in Table 8. 
 
After a median follow-up time of 45 months, the final OS analysis was performed based on 310 events 
(60% of randomised patients). A 6.9-month difference in median OS in the palbociclib plus fulvestrant 
arm compared with the placebo plus fulvestrant arm was observed; this result was not statistically 
significant at the prespecified significance level of 0.0235 (1-sided). In the placebo plus fulvestrant 
arm, 15.5% of randomised patients received palbociclib and other CDK inhibitors as post progression 
subsequent treatments. 
 
The results from the investigator-assessed PFS and final OS data from PALOMA-3 study are 
presented in Table 8. The relevant Kaplan-Meier plots are shown in Figures 2 and 3, respectively. 
 
Table 8. Efficacy results – PALOMA-3 study (investigator assessment, intent-to-treat 

population) 
 Updated analysis 

(23 October 2015 cutoff) 
 IBRANCE 

plus fulvestrant 
(N=347) 

Placebo 
plus fulvestrant 

(N=174) 
Progression-free survival (PFS) 
    Number of events (%) 200 (57.6) 133 (76.4) 
 Median [months (95% CI)]  11.2 (9.5, 12.9) 4.6 (3.5, 5.6) 
 Hazard ratio (95% CI) and p-value 0.497 (0.398, 0.620), p< 0.000001
Secondary efficacy endpoints  
OR [% (95% CI)] 26.2 (21.7, 31.2) 13.8 (9.0, 19.8)
OR (measurable disease) [% (95% CI)] 33.7 (28.1, 39.7) 17.4 (11.5, 24.8)
CBR [% (95% CI)] 68.0 (62.8, 72.9) 39.7 (32.3, 47.3)
Final overall survival (OS) 
(13 April 2018 cutoff) 
Number of events (%) 201 (57.9) 109 (62.6) 
Median [months (95% CI)] 34.9 (28.8, 40.0) 28.0 (23.6, 34.6) 
Hazard ratio (95% CI) and p-value† 0.814 (0.644, 1.029) 

p=0.0429†* 
CBR=clinical benefit response; CI=confidence interval; N=number of patients; OR=objective response.  
Secondary endpoint results are based on confirmed and unconfirmed responses according to RECIST 1.1. 
* Not statistically significant.  
† 1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to prior 
endocrine therapy per randomisation. 
 



39 

Figure 2. Kaplan-Meier plot of progression-free survival (investigator assessment, 
intent-to-treat population) – PALOMA-3 study (23 October 2015 cutoff) 

0 2 4 6 8 10 12 14 16 18 20 22
Time (Month)

0

10

20

30

40

50

60

70

80

90

100

Pr
og

re
ss

io
n-

Fr
ee

 S
ur

vi
va

l P
ro

ba
bi

lit
y 

(%
)

palbociclib+fulvestrant
placebo+fulvestrant

347 276 245 215 189 168 137 69 38 12 2 1PAL+FUL
174 112 83 62 51 43 29 15 11 4 1PCB+FUL

Number of patients at risk

 
FUL=fulvestrant; PAL=palbociclib; PCB=placebo. 
 
A reduction in the risk of disease progression or death in the palbociclib plus fulvestrant arm was 
observed in all individual patient subgroups defined by stratification factors and baseline 
characteristics. This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 0.75]) 
and postmenopausal women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with visceral site of 
metastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of 
0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in the 
metastatic setting, whether 0 (HR of 0.59 [95% CI: 0.37, 0.93]), 1 (HR of 0.46 [95% CI: 0.32, 
0.64]), 2 (HR of 0.48 [95% CI: 0.30, 0.76]), or ≥ 3 lines (HR of 0.59 [95% CI: 0.28, 1.22]).  
 
Figure 3. Kaplan-Meier plot of overall survival (intent-to-treat population) – PALOMA-3 

study (13 April 2018 cutoff) 

0 6 12 18 24 30 36 42 48 54
Time (Month)

0

10

20

30

40

50

60

70

80

90

100

O
ve

ra
ll 

Su
rv

iv
al

 P
ro

ba
bi

lit
y 

(%
)

palbociclib+fulvestrant
placebo+fulvestrant

347 321 286 247 209 165 148 126 17PAL+FUL
174 155 135 115 86 68 57 43 7PCB+FUL

Number of patients at risk

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



40 

 
Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without 
visceral disease are displayed in Table 9. 
 
Table 9. Efficacy results in visceral and non-visceral disease from PALOMA–3 study 

(intent-to-treat population) 
 Visceral disease Non-visceral disease 
 IBRANCE 

plus 
fulvestrant 

(N=206) 

Placebo 
plus 

fulvestrant 
(N=105) 

IBRANCE 
plus 

fulvestrant 
(N=141) 

Placebo 
plus 

fulvestrant 
(N=69) 

OR [%, (95% CI)]  35.0 
(28.5, 41.9) 

13.3 
(7.5, 21.4) 

13.5 
(8.3, 20.2) 

14.5 
(7.2, 25.0) 

TTR, Median [months 
(range)] 

3.8 
(3.5, 16.7) 

5.4 
(3.5, 16.7) 

3.7 
(1.9, 13.7) 

3.6 
(3.4, 3.7) 

N=number of patients; CI=confidence interval; OR= objective response based on confirmed and unconfirmed 
responses according to RECIST 1.1; TTR=time to first tumour response.
 
Patient-reported symptoms were assessed using the European Organisation for Research and 
Treatment of Cancer (EORTC) quality of life questionnaire (QLQ)-C30 and its Breast Cancer Module 
(EORTC QLQ-BR23). A total of 335 patients in the palbociclib plus fulvestrant arm and 166 patients 
in the fulvestrant only arm completed the questionnaire at baseline and at least 1 postbaseline visit. 
 
Time-to-Deterioration was prespecified as time between baseline and first occurrence of ≥ 10 points 
increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a 
symptom benefit by significantly delaying time-to-deterioration in pain symptom compared with 
placebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85]; 
p< 0.001).   
 
The European Medicines Agency has waived the obligation to submit the results of studies with 
IBRANCE in all subsets of the paediatric population in the treatment of breast carcinoma (see 
section 4.2 for information on paediatric use). 
 
5.2 Pharmacokinetic properties 
 
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.  
 



41 

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 
 
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 sulphonation, with acylation 
and glucuronidation contributing as minor pathways. Palbociclib was the major circulating 
drug-derived entity in plasma.  
 
The majority of the material was excreted as metabolites. In faeces, 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 
sulphotransferase (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 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 92% of the total administered radioactive 
dose was recovered in 15 days; faeces (74% of dose) was the major route of excretion, with 17% of 
the dose recovered in urine. Excretion of unchanged palbociclib in faeces and urine was 2% and 7% of 
the administered dose, respectively. 
 
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. 
 
In vitro evaluations indicate that palbociclib has low potential to inhibit the activities of organic anion 
transporter (OAT)1, OAT3, organic cation transporter (OCT)2, organic anion transporting polypeptide 
(OATP)1B1, OATP1B3, and bile salt export pump (BSEP) at clinically relevant concentrations.  
 
Special populations 
 
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 38 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. 
 
Paediatric population 
Pharmacokinetics of palbociclib has not been evaluated in patients < 18 years of age. 
 
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 (Child-Pugh class C) hepatic impairment, 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, 



42 

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 × ULN 
and any AST), mild hepatic impairment had no effect on the pharmacokinetics of palbociclib. 
 
Renal impairment 
Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total 
palbociclib exposure (AUCinf) 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 pharmacokinetics of 
palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring 
haemodialysis. 
 
Ethnicity 
In a pharmacokinetic study in healthy volunteers, palbociclib 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 Japanese or 
Asian breast cancer patients after multiple dosing. Based on an analysis of the cumulative 
pharmacokinetic, safety, and efficacy data across Asian and non-Asian populations, no dose 
adjustment based on Asian race is considered necessary. 
 
5.3 Preclinical safety data 
 
The primary target organ findings of potential relevance to humans included haematolymphopoietic 
and male reproductive organ effects in rats and dogs in studies up to 39 weeks duration. Effects on 
glucose metabolism were associated with findings in the pancreas and secondary effects on eye, teeth, 
kidney, and adipose tissue in studies ≥ 15 weeks duration in rats only and bone changes were observed 
in rats only following 27 weeks of dosing. These systemic toxicities were generally observed at 
clinically relevant exposures based on AUC. 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. The reversibility of the effects 
on glucose homeostasis, pancreas, eye, kidney, and bone was not established following a 12-week 
nondosing period, whereas partial to full reversal of effects on the haematolymphopoietic and male 
reproductive systems, teeth, and adipose tissue was observed. 
 
Carcinogenicity 
 
Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat 
study. Palbociclib was negative for carcinogenicity in transgenic mice at doses up to 60 mg/kg/day 
(No Observed Effect Level [NOEL] approximately 11 times human clinical exposure based on AUC). 
Palbociclib-related neoplastic finding in rats included an increased incidence of microglial cell 
tumours in the central nervous system of males at 30 mg/kg/day; there were no neoplastic findings in 
female rats at any dose up to 200 mg/kg/day. The NOEL for palbociclib-related carcinogenicity effects 
was 10 mg/kg/day (approximately 2 times the human clinical exposure based on AUC) and 
200 mg/kg/day (approximately 4 times the human clinical exposure based on AUC) in males and 
females, respectively. The relevance of the male rat neoplastic finding to humans is unknown. 
 



43 

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 exposure of animals at 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 non-clinical 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, respectively. Partial reversibility of male reproductive organ 
effects was observed in the rat and dog following a 4- and 12-week nondosing 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 is a reversible inhibitor of cyclin-dependent kinases 4 and 6, which are both involved in 
regulating the cell cycle. It may therefore have risk of foetal harm if used during pregnancy. 
Palbociclib was foetotoxic 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 foetal 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 foetal exposure and 
cross-placenta transfer have not been examined.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core  
 
Microcrystalline cellulose 
Colloidal silicon dioxide  
Crospovidone 
Magnesium stearate 
Succinic acid  
 



44 

Film-coating 
 
Hypromellose (E464) 
Titanium dioxide (E171) 
Triacetin  
Indigo carmine aluminum lake (E132) 
Iron oxide red (E172) (75 mg and 125 mg tablets only) 
Iron oxide yellow (E172) (100 mg tablets only) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special temperature storage conditions. 
Store in the original blister package in order to protect from moisture. 
 
6.5 Nature and contents of container 
 
PVC/OPA/Al/PVC/Al blister containing 7 film-coated tablets (1 film-coated tablet per cell). Each 
carton contains 21 film-coated tablets (3 blisters per carton) or 63 film-coated tablets (9 blisters per 
carton).  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
IBRANCE 75 mg film-coated tablets 
EU/1/16/1147/010  (21 film-coated tablets in carton) 
EU/1/16/1147/011  (63 film-coated tablets in carton) 
 
IBRANCE 100 mg film-coated tablets 
EU/1/16/1147/012  (21 film-coated tablets in carton) 
EU/1/16/1147/013  (63 film-coated tablets in carton) 
 
IBRANCE 125 mg film-coated tablets 
EU/1/16/1147/014  (21 film-coated tablets in carton) 
EU/1/16/1147/015  (63 film-coated tablets in carton) 



45 

 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 09 November 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



46 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE  
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 



47 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
GERMANY 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
 Periodic safety update reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 
Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 6 months following authorisation.  
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile 
or as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 
 
 
 



48 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



49 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



50 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – 75 MG CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg hard capsules  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 75 mg palbociclib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 hard capsules 
63 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



51 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/001 (21 hard capsules) 
EU/1/16/1147/007 (63 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 



52 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
75 MG CAPSULES  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg hard capsules  
palbociclib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



53 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL – 75 MG CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg hard capsules  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 75 mg palbociclib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



54 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



55 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – 100 MG CAPSULES  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 100 mg hard capsules  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 100 mg palbociclib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 hard capsules 
63 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



56 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/003 (21 hard capsules) 
EU/1/16/1147/008 (63 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



57 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
100 MG CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 100 mg hard capsules  
palbociclib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



58 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL – 100 MG CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 100 mg hard capsules 
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 100 mg palbociclib.  
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



59 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



60 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON – 125 MG CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 125 mg hard capsules  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 125 mg palbociclib.  
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 hard capsules 
63 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



61 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/005 (21 hard capsules) 
EU/1/16/1147/009 (63 hard capsules) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 125 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



62 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
125 MG CAPSULES  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 125 mg hard capsules  
palbociclib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



63 

PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL – 125 MG CAPSULES 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 125 mg hard capsules  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each capsule contains 125 mg palbociclib. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. See leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 hard capsules 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



64 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 125 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



65 

 
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – 75 MG TABLETS CARTON FOR BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg film-coated tablets  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 75 mg palbociclib. 
 
 
3. LIST OF EXCIPIENTS 
 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 film-coated tablets in blisters 
63 film-coated tablets in blisters 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original blister package in order to protect from moisture. 
 
 



66 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/010 (21 film-coated tablets) 
EU/1/16/1147/011 (63 film-coated tablets) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 75 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 



67 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
75 MG TABLETS  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 75 mg tablets  
palbociclib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



68 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – 100 MG TABLETS CARTON FOR BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 100 mg film-coated tablets  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 100 mg palbociclib. 
 
 
3. LIST OF EXCIPIENTS 
 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 film-coated tablets in blisters 
63 film-coated tablets in blisters 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original blister package in order to protect from moisture. 
 
 



69 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/012 (21 film-coated tablets) 
EU/1/16/1147/013 (63 film-coated tablets) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 100 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



70 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
100 MG TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 100 mg tablets  
palbociclib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



71 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON – 125 MG TABLETS CARTON FOR BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 125 mg film-coated tablets  
palbociclib 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 125 mg palbociclib.  
 
 
3. LIST OF EXCIPIENTS 
 
See the package leaflet for further information.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
21 film-coated tablets in blisters 
63 film-coated tablets in blisters 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original blister package in order to protect from moisture. 
 
 



72 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1147/014 (21 film-coated tablets) 
EU/1/16/1147/015 (63 film-coated tablets) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
IBRANCE 125 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



73 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
125 MG TABLETS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
IBRANCE 125 mg tablets 
palbociclib 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



74 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



75 

Package leaflet: Information for the patient 
 

IBRANCE 75 mg hard capsules 
IBRANCE 100 mg hard capsules 
IBRANCE 125 mg hard capsules 

palbociclib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What IBRANCE is and what it is used for  
2. What you need to know before you take IBRANCE 
3. How to take IBRANCE 
4. Possible side effects 
5. How to store IBRANCE 
6. Contents of the pack and other information 
 
 
1. What IBRANCE is and what it is used for 
 
IBRANCE is an anticancer medicine containing the active substance palbociclib.  
 
Palbociclib works by blocking proteins called cyclin-dependent kinase 4 and 6, which regulate cell 
growth and division. Blocking these proteins can slow down growth of cancer cells and delay the 
progression of your cancer.  
 
IBRANCE is used to treat patients with certain types of breast cancer (hormone receptor-positive, 
human epidermal growth factor receptor 2-negative) which have spread beyond the original tumour 
and/or to other organs. It is given together with aromatase inhibitors or fulvestrant, which are used as 
hormonal anticancer therapies. 
 
 
2. What you need to know before you take IBRANCE  
 
Do not take IBRANCE: 
 

- if you are allergic to palbociclib or any of the other ingredients of this medicine (listed in 
section 6).  

- use of preparations containing St. John’s Wort should be avoided while you are taking 
IBRANCE. 

 
Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before taking IBRANCE. 
 



76 

IBRANCE may reduce the number of your white blood cells and weaken your immune system. 
Therefore, you may be at greater risk of getting an infection while you are taking IBRANCE. 
 
Tell your doctor, pharmacist or nurse if you experience signs or symptoms of an infection, such as 
chills or fever. 
 
You will have regular blood tests during treatment to check whether IBRANCE affects your blood 
cells (white blood cells, red blood cells, and platelets).  
 
IBRANCE may cause severe or life-threatening inflammation of the lungs during treatment that can 
lead to death. Tell your healthcare provider right away if you have any new or worsening symptoms 
including: 

 difficulty breathing or shortness of breath 
 dry cough  
 chest pain 

 
Children and adolescents 
 
IBRANCE is not to be used in children or adolescents (under 18 years of age). 
 
Other medicines and IBRANCE 
 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. IBRANCE may affect the way some other medicines work. 
 
In particular, the following may increase the risk of side effects with IBRANCE: 

 Lopinavir, indinavir, nelfinavir, ritonavir, telaprevir, and saquinavir used to treat HIV 
infection/AIDS. 

 Clarithromycin and telithromycin antibiotics used to treat bacterial infections.  
 Voriconazole, itraconazole, ketoconazole, and posaconazole used to treat fungal infections. 
 Nefazodone used to treat depression. 

 
The following medicines may have increased risk of side effects when given with IBRANCE:  

 Quinidine generally used to treat heart rhythm problems. 
 Colchicine used to treat gout. 
 Pravastatin and rosuvastatin used to treat high cholesterol levels. 
 Sulfasalazine used to treat rheumatoid arthritis. 
 Alfentanil used for anaesthesia in surgery; fentanyl used in pre-procedures as a pain reliever as 

well as an anaesthetic. 
 Cyclosporine, everolimus, tacrolimus, and sirolimus used in organ transplantation to prevent 

rejection. 
 Dihydroergotamine and ergotamine used to treat migraine. 
 Pimozide used to treat schizophrenia and chronic psychosis. 
 

The following medicines may reduce the effectiveness of IBRANCE:  
 Carbamazepine and phenytoin, used to stop seizures or fits. 
 Enzalutamide to treat prostate cancer. 
 Rifampin used to treat tuberculosis (TB). 
 St. John’s Wort, an herbal product used to treat mild depression and anxiety. 

  
IBRANCE with food and drink 
 
Avoid grapefruit and grapefruit juice while you are taking IBRANCE as it may increase the side 
effects of IBRANCE. 
 



77 

Pregnancy and breast-feeding and fertility 
 
You should not use IBRANCE if you are pregnant. 
 
You should avoid becoming pregnant while taking IBRANCE. 
 
Discuss contraception with your doctor if there is any possibility that you or your partner may become 
pregnant.  
 
If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Women of childbearing potential who are receiving this medicinal product, or their male partners 
should use adequate contraceptive methods (e.g., double-barrier contraception such as condom and 
diaphragm). These methods should be used during therapy and for at least 3 weeks after completing 
therapy for females and for at least 14 weeks for males. 
 
Breast-feeding 
You should not breast-feed while taking IBRANCE. It is not known if IBRANCE is excreted in breast 
milk. 
 
Fertility 
Palbociclib may decrease fertility in men. 
 
Therefore, men may consider sperm preservation before taking IBRANCE. 
 
Driving and using machines 
 
Tiredness is a very common side effect. If you feel unusually tired, take special care when driving or 
using machines. 
 
IBRANCE contains lactose  
This medicine contains lactose (found in milk or dairy products). If you have been told by your doctor 
that you have an intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take IBRANCE 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
The recommended dose is 125 mg of IBRANCE taken once a day for 3 weeks followed by 1 week 
without taking IBRANCE. Your doctor will tell you how many capsules of IBRANCE to take. 
 
If you experience certain side effects while you are taking IBRANCE (see section 4 “Possible side 
effects”), your doctor may lower your dose or stop treatment, either temporarily or permanently. The 
dose may be lowered to one of the other available strengths 100 mg or 75 mg. 
 
Take IBRANCE once a day at about the same time every day with food, preferably a meal. 
 
Swallow the capsule whole with a glass of water. Do not chew or crush the capsules. Do not open the 
capsules. 
 
If you take more IBRANCE than you should 
 
If you have taken too much IBRANCE, see a doctor or go to a hospital immediately. Urgent treatment 
may be necessary. 



78 

 
Take the carton and this leaflet, so that the doctor knows what you have been taking. 
 
If you forget to take IBRANCE 
 
If you miss a dose or vomit, take your next dose as scheduled. Do not take a double dose to make up 
for the forgotten capsules. 
 
If you stop taking IBRANCE 
 
Do not stop taking IBRANCE unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them: 
 
Contact your doctor immediately if you have any of these symptoms:  

 fever, chills, weakness, shortness of breath, bleeding, or easy bruising which could be a sign of 
a serious blood disorder. 

 difficulty breathing, dry cough or chest pain which could be a sign of inflammation of the 
lungs.  

 
Other side effects with IBRANCE may include: 
 
Very common side effects (may affect more than 1 in 10 people): 
 Infections 
 Reduction in white blood cells, red blood cells, and blood platelets 
 Feeling of tiredness 
 Decreased appetite  
 Inflammation of the mouth and lips (stomatitis), nausea, vomiting, diarrhoea 
 Rash 
 Hair loss 
 Weakness 
 Fever 
 Abnormalities in liver blood tests 
 Dry skin 
 
Common side effects (may affect up to 1 in 10 people): 
 Fever with a drop in the white blood cell count (febrile neutropenia) 
 Blurred vision, increased tearing, dry eye 
 Alteration in taste (dysgeusia)  
 Nosebleed 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects, you can help provide more information on the 
safety of this medicine. 
 
 



79 

5. How to store IBRANCE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the bottle or blister and carton after 
“EXP”. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What IBRANCE contains  
- The active substance is palbociclib. IBRANCE hard capsules come in different strengths. 
- IBRANCE 75 mg hard capsule: each capsule contains 75 mg palbociclib. 
- IBRANCE 100 mg hard capsule: each capsule contains 100 mg palbociclib. 
- IBRANCE 125 mg hard capsule: each capsule contains 125 mg palbociclib. 
- The other ingredients are: 

Capsule content: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate type A, 
colloidal anhydrous silica, magnesium stearate. Capsule shell: gelatin, red iron oxide (E172), 
yellow iron oxide (E172), titanium dioxide (E171). Printing ink: shellac, titanium dioxide (E171), 
ammonium hydroxide (28% solution), propylene glycol, simeticone (see section 2 “IBRANCE 
contains lactose”). 

 
What IBRANCE looks like and contents of the pack 
- IBRANCE 75 mg is supplied as opaque, hard capsules, with a light orange body (printed 

“PBC 75” in white) and a light orange cap (printed “Pfizer” in white). 
- IBRANCE 100 mg is supplied as opaque, hard capsules, with a light orange body (printed 

“PBC 100” in white) and a caramel cap (printed “Pfizer” in white). 
- IBRANCE 125 mg is supplied as opaque, hard capsules, with a caramel body (printed “PBC 125” 

in white) and a caramel cap (printed “Pfizer” in white). 
 
IBRANCE 75 mg, 100 mg, and 125 mg are available in blister packs of 21 or 63 hard capsules and in 
plastic bottles of 21 hard capsules. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 



80 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
Belgique / België /Belgien 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. + 370 52 51 4000 
 

България 
Пфайзер Люксембург САРЛ, Клон България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 
 

Česká republika 
Pfizer PFE, spol. s r.o. 
Tel.: +420-283-004-111 

Magyarország 
Pfizer Kft. 
Tel.: +36-1-488-37-00 
 

Danmark 
Pfizer ApS 
Tlf: +45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel: +356 21344610 
 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055 51000  

Nederland 
Pfizer BV 
Tel: +31 (0)10 406 43 01 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 
 

Norge 
Pfizer Norge AS 
Tlf: +47 67 52 61 00 
 

Ελλάδα 
Pfizer Ελλάς A.E. 
Τλ: +30 210 6785 800 
 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 
 

España 
Pfizer, S.L. 
Tel: +34 91 490 99 00 

Polska 
Pfizer Polska Sp. z o.o. 
Tel.:+48 22 335 61 00 
 

France 
Pfizer  
Tél: +33 (0)1 58 07 34 40 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 
 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 

România 
Pfizer Romania S.R.L. 
Tel: +40 (0) 21 207 28 00 
 

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free) 
+44 (0)1304 616161 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel.: + 386 (0)1 52 11 400 
 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel.: + 421 2 3355 5500 
 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh./Tel: +358 (0)9 43 00 40 



81 

Kύπρος 
Pfizer Ελλάς Α.Ε. (Cyprus Branch) 
Tηλ+357 22 817690 

Sverige  
Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel.: + 371 670 35 775 
 

United Kingdom 
Pfizer Limited 
Tel: +44 (0) 1304 616161 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 



82 

 
Package leaflet: Information for the patient 

 
IBRANCE 75 mg film-coated tablets 
IBRANCE 100 mg film-coated tablets 
IBRANCE 125 mg film-coated tablets 

palbociclib 
 

This medicine is subject to additional monitoring. This will allow quick identification of new 
safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What IBRANCE is and what it is used for  
2. What you need to know before you take IBRANCE 
3. How to take IBRANCE 
4. Possible side effects 
5. How to store IBRANCE 
6. Contents of the pack and other information 
 
 
1. What IBRANCE is and what it is used for 
 
IBRANCE is an anticancer medicine containing the active substance palbociclib.  
 
Palbociclib works by blocking proteins called cyclin-dependent kinase 4 and 6, which regulate cell 
growth and division. Blocking these proteins can slow down growth of cancer cells and delay the 
progression of your cancer.  
 
IBRANCE is used to treat patients with certain types of breast cancer (hormone receptor-positive, 
human epidermal growth factor receptor 2-negative) which have spread beyond the original tumour 
and/or to other organs. It is given together with aromatase inhibitors or fulvestrant, which are used as 
hormonal anticancer therapies. 
 
 
2. What you need to know before you take IBRANCE  
 
Do not take IBRANCE: 
 

- if you are allergic to palbociclib or any of the other ingredients of this medicine (listed in 
section 6).  

- use of preparations containing St. John’s Wort should be avoided while you are taking 
IBRANCE. 

 
Warnings and precautions  
 
Talk to your doctor, pharmacist or nurse before taking IBRANCE. 



83 

 
IBRANCE may reduce the number of your white blood cells and weaken your immune system. 
Therefore, you may be at greater risk of getting an infection while you are taking IBRANCE. 
 
Tell your doctor, pharmacist or nurse if you experience signs or symptoms of an infection, such as 
chills or fever. 
 
You will have regular blood tests during treatment to check whether IBRANCE affects your blood 
cells (white blood cells, red blood cells, and platelets).  
 
IBRANCE may cause severe or life-threatening inflammation of the lungs during treatment that can 
lead to death. Tell your healthcare provider right away if you have any new or worsening symptoms 
including: 

 difficulty breathing or shortness of breath 
 dry cough  
 chest pain 

 
Children and adolescents 
 
IBRANCE is not to be used in children or adolescents (under 18 years of age). 
 
Other medicines and IBRANCE 
 
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines. IBRANCE may affect the way some other medicines work. 
 
In particular, the following may increase the risk of side effects with IBRANCE: 

 Lopinavir, indinavir, nelfinavir, ritonavir, telaprevir, and saquinavir used to treat HIV 
infection/AIDS. 

 Clarithromycin and telithromycin antibiotics used to treat bacterial infections.  
 Voriconazole, itraconazole, ketoconazole, and posaconazole used to treat fungal infections. 
 Nefazodone used to treat depression. 

 
The following medicines may have increased risk of side effects when given with IBRANCE:  

 Quinidine generally used to treat heart rhythm problems. 
 Colchicine used to treat gout. 
 Pravastatin and rosuvastatin used to treat high cholesterol levels. 
 Sulfasalazine used to treat rheumatoid arthritis. 
 Alfentanil used for anaesthesia in surgery; fentanyl used in pre-procedures as a pain reliever as 

well as an anaesthetic. 
 Cyclosporine, everolimus, tacrolimus, and sirolimus used in organ transplantation to prevent 

rejection. 
 Dihydroergotamine and ergotamine used to treat migraine. 
 Pimozide used to treat schizophrenia and chronic psychosis. 
 

The following medicines may reduce the effectiveness of IBRANCE:  
 Carbamazepine and phenytoin, used to stop seizures or fits. 
 Enzalutamide to treat prostate cancer. 
 Rifampin used to treat tuberculosis (TB). 
 St. John’s Wort, an herbal product used to treat mild depression and anxiety. 

 
IBRANCE with food and drink 
 
Avoid grapefruit and grapefruit juice while you are taking IBRANCE as it may increase the side 
effects of IBRANCE.  
 



84 

Pregnancy and breast-feeding and fertility 
 
You should not use IBRANCE if you are pregnant. 
 
You should avoid becoming pregnant while taking IBRANCE. 
 
Discuss contraception with your doctor if there is any possibility that you or your partner may become 
pregnant.  
 
If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Women of childbearing potential who are receiving this medicinal product, or their male partners 
should use adequate contraceptive methods (e.g., double-barrier contraception such as condom and 
diaphragm). These methods should be used during therapy and for at least 3 weeks after completing 
therapy for females and for at least 14 weeks for males. 
 
Breast-feeding 
You should not breast-feed while taking IBRANCE. It is not known if IBRANCE is excreted in breast 
milk. 
 
Fertility 
Palbociclib may decrease fertility in men. 
 
Therefore, men may consider sperm preservation before taking IBRANCE. 
 
Driving and using machines 
 
Tiredness is a very common side effect. If you feel unusually tired, take special care when driving or 
using machines. 
 
 
3. How to take IBRANCE 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  
 
The recommended dose is 125 mg of IBRANCE taken once a day for 3 weeks followed by 1 week 
without taking IBRANCE. Your doctor will tell you how many tablets of IBRANCE to take. 
 
If you experience certain side effects while you are taking IBRANCE (see section 4 “Possible side 
effects”), your doctor may lower your dose or stop treatment, either temporarily or permanently. The 
dose may be lowered to one of the other available strengths 100 mg or 75 mg. 
 
Take IBRANCE once a day at about the same time every day with or without food. 
 
Swallow the tablet whole with a glass of water. Do not chew or crush the tablets. Do not split the 
tablets prior to swallowing. No tablet should be ingested if it is broken, cracked, or otherwise not 
intact. 
 
If you take more IBRANCE than you should 
 
If you have taken too much IBRANCE, see a doctor or go to a hospital immediately. Urgent treatment 
may be necessary. 
 
Take the carton and this leaflet, so that the doctor knows what you have been taking. 
 



85 

If you forget to take IBRANCE 
 
If you miss a dose or vomit, take your next dose as scheduled. Do not take a double dose to make up 
for the forgotten tablets. 
 
If you stop taking IBRANCE 
 
Do not stop taking IBRANCE unless your doctor tells you to. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them: 
 
Contact your doctor immediately if you have any of these symptoms:  

 fever, chills, weakness, shortness of breath, bleeding, or easy bruising which could be a sign of 
a serious blood disorder. 

 difficulty breathing, dry cough or chest pain which could be a sign of inflammation of the 
lungs. 

 
Other side effects with IBRANCE may include: 
 
Very common side effects (may affect more than 1 in 10 people): 
 Infections 
 Reduction in white blood cells, red blood cells, and blood platelets 
 Feeling of tiredness 
 Decreased appetite  
 Inflammation of the mouth and lips (stomatitis), nausea, vomiting, diarrhoea 
 Rash 
 Hair loss 
 Weakness 
 Fever 
 Abnormalities in liver blood tests 
 Dry skin 
 
Common side effects (may affect up to 1 in 10 people): 
 Fever with a drop in the white blood cell count (febrile neutropenia) 
 Blurred vision, increased tearing, dry eye 
 Alteration in taste (dysgeusia)  
 Nosebleed 
  
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store IBRANCE 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the blister and carton after “EXP”. 
The expiry date refers to the last day of that month. 



86 

 
This medicinal product does not require any special temperature storage conditions. Store in the 
original blister package in order to protect from moisture. 
 
Do not use this medicine if you notice that the pack is damaged or shows signs of tampering. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What IBRANCE contains  
 
- The active substance is palbociclib. IBRANCE film-coated tablets come in different strengths. 
- IBRANCE 75 mg film-coated tablet: each tablet contains 75 mg palbociclib. 
- IBRANCE 100 mg film-coated tablet: each tablet contains 100 mg palbociclib. 
- IBRANCE 125 mg film-coated tablet: each tablet contains 125 mg palbociclib. 
- The other ingredients are: 
 Tablet core: microcrystalline cellulose, colloidal silicon dioxide, crospovidone, magnesium 

stearate, succinic acid. 
 Film-coating: hypromellose (E464), titanium dioxide (E171), triacetin, Indigo carmine 

aluminum lake (E132), iron oxide red (E172) (75 mg and 125 mg tablets only), iron oxide 
yellow (E172) (100 mg tablets only). 

 
What IBRANCE looks like and contents of the pack 
 
- IBRANCE 75 mg tablets are supplied as round, light purple, film-coated tablets with “Pfizer” on 

one side and “PBC 75” on the other side.  
- IBRANCE 100 mg tablets are supplied as oval, green, film-coated tablets with “Pfizer” on one 

side and “PBC 100” on the other side. 
- IBRANCE 125 mg tablets are supplied as oval, light purple, film-coated tablets with “Pfizer” on 

one side and “PBC 125” on the other side.  
 
IBRANCE 75 mg, 100 mg, and 125 mg are available in blister packs of 21 tablets or 63 tablets in a 
carton.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
Manufacturer 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 



87 

Belgique / België /Belgien 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. + 370 52 51 4000 
 

България 
Пфайзер Люксембург САРЛ, Клон България 
Тел.: +359 2 970 4333 

Luxembourg/Luxemburg 
Pfizer S.A. 
Tél/Tel: +32 (0)2 554 62 11 
 

Česká republika 
Pfizer PFE, spol. s r.o. 
Tel.: +420-283-004-111 

Magyarország 
Pfizer Kft. 
Tel.: +36-1-488-37-00 
 

Danmark 
Pfizer ApS 
Tlf: +45 44 20 11 00 

Malta 
Vivian Corporation Ltd. 
Tel: +356 21344610 
 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055 51000  

Nederland 
Pfizer BV 
Tel: +31 (0)10 406 43 01 
 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 
 

Norge 
Pfizer Norge AS 
Tlf: +47 67 52 61 00 
 

Ελλάδα 
Pfizer Ελλάς A.E. 
Τλ: +30 210 6785 800 
 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 
 

España 
Pfizer, S.L. 
Tel: +34 91 490 99 00 

Polska 
Pfizer Polska Sp. z o.o. 
Tel.:+48 22 335 61 00 

France 
Pfizer  
Tél: +33 (0)1 58 07 34 40 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 

Hrvatska 
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 

România 
Pfizer Romania S.R.L. 
Tel: +40 (0) 21 207 28 00 
 

Ireland 
Pfizer Healthcare Ireland 
Tel: 1800 633 363 (toll free) 
+44 (0)1304 616161 

Slovenija 
Pfizer Luxembourg SARL 
Pfizer, podružnica za svetovanje s področja 
farmacevtske dejavnosti, Ljubljana 
Tel.: + 386 (0)1 52 11 400 
 

Ísland 
Icepharma hf. 
Sími: +354 540 8000 

Slovenská republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel.: + 421 2 3355 5500 
 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 

Suomi/Finland 
Pfizer Oy 
Puh./Tel: +358 (0)9 43 00 40 
 



88 

Kύπρος 
Pfizer Ελλάς Α.Ε. (Cyprus Branch) 
Tηλ+357 22 817690 

Sverige  
Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel.: + 371 670 35 775 
 

United Kingdom 
Pfizer Limited 
Tel: +44 (0) 1304 616161 
 

 
This leaflet was last revised in  
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 
 
 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETINGAUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
{'Title': '1. what ibrance is and what it is used for', 'Section_Content': 'ibrance is an anticancer medicine containing the active substance palbociclib. palbociclib works by blocking proteins called cyclin-dependent kinase 4 and 6, which regulate cell growth and division. blocking these proteins can slow down growth of cancer cells and delay the progression of your cancer. ibrance is used to treat patients with certain types of breast cancer (hormone receptor-positive, human epidermal growth factor receptor 2-negative) which have spread beyond the original tumour and/or to other organs. it is given together with aromatase inhibitors or fulvestrant, which are used as hormonal anticancer therapies.', 'Entity_Recognition': [{'Text': 'ibrance', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 1, 'BeginOffset': 0, 'EndOffset': 7, 'Score': 0.5847988724708557, 'Text': 'ibrance', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': []}, {'Text': 'an anticancer medicine', 'Type': 'TREATMENT', 'BeginOffset': 11, 'EndOffset': 33}, {'Text': 'the active substance palbociclib', 'Type': 'TREATMENT', 'BeginOffset': 45, 'EndOffset': 77}, {'Id': 3, 'BeginOffset': 79, 'EndOffset': 90, 'Score': 0.9875812530517578, 'Text': 'palbociclib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'cyclin-dependent kinase', 'Type': 'TREATMENT', 'BeginOffset': 125, 'EndOffset': 148}, {'Text': '4', 'Type': 'NUMBER', 'BeginOffset': 149, 'EndOffset': 150}, {'Text': '6', 'Type': 'NUMBER', 'BeginOffset': 155, 'EndOffset': 156}, {'Text': 'blocking these proteins', 'Type': 'PROBLEM', 'BeginOffset': 199, 'EndOffset': 222}, {'Text': 'cancer cells', 'Type': 'PROBLEM', 'BeginOffset': 247, 'EndOffset': 259}, {'Text': 'your cancer', 'Type': 'PROBLEM', 'BeginOffset': 289, 'EndOffset': 300}, {'Text': 'ibrance', 'Type': 'TREATMENT', 'BeginOffset': 302, 'EndOffset': 309}, {'Id': 7, 'BeginOffset': 358, 'EndOffset': 371, 'Score': 0.9328979253768921, 'Text': 'breast cancer', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.9810733795166016}]}, {'Text': 'hormone receptor', 'Type': 'TEST', 'BeginOffset': 373, 'EndOffset': 389}, {'Text': 'human epidermal growth factor receptor', 'Type': 'TEST', 'BeginOffset': 400, 'EndOffset': 438}, {'Id': 8, 'BeginOffset': 489, 'EndOffset': 495, 'Score': 0.566865086555481, 'Text': 'tumour', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'DIAGNOSIS', 'Score': 0.6932195425033569}]}, {'Id': 4, 'BeginOffset': 546, 'EndOffset': 566, 'Score': 0.5056790709495544, 'Text': 'aromatase inhibitors', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 5, 'BeginOffset': 570, 'EndOffset': 581, 'Score': 0.9979007244110107, 'Text': 'fulvestrant', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Id': 10, 'BeginOffset': 601, 'EndOffset': 630, 'Score': 0.95904541015625, 'Text': 'hormonal anticancer therapies', 'Category': 'TEST_TREATMENT_PROCEDURE', 'Type': 'TREATMENT_NAME', 'Traits': []}]}
{'Title': '2. what you need to know before you take ibrance', 'Section_Content': "do not take ibrance: - if you are allergic to palbociclib or any of the other ingredients of this medicine (listed in section 6). - use of preparations containing st. john's wort should be avoided while you are taking ibrance. warnings and precautions talk to your doctor, pharmacist or nurse before taking ibrance. ibrance may reduce the number of your white blood cells and weaken your immune system. therefore, you may be at greater risk of getting an infection while you are taking ibrance. tell your doctor, pharmacist or nurse if you experience signs or symptoms of an infection, such as chills or fever. you will have regular blood tests during treatment to check whether ibrance affects your blood cells (white blood cells, red blood cells, and platelets). ibrance may cause severe or life-threatening inflammation of the lungs during treatment that can lead to death. tell your healthcare provider right away if you have any new or worsening symptoms including: difficulty breathing or shortness of breath dry cough chest pain children and adolescents ibrance is not to be used in children or adolescents (under 18 years of age). other medicines and ibrance tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines. ibrance may affect the way some other medicines work. in particular, the following may increase the risk of side effects with ibrance: lopinavir, indinavir, nelfinavir, ritonavir, telaprevir, and saquinavir used to treat hiv infection/aids. clarithromycin and telithromycin antibiotics used to treat bacterial infections. voriconazole, itraconazole, ketoconazole, and posaconazole used to treat fungal infections. nefazodone used to treat depression. the following medicines may have increased risk of side effects when given with ibrance: quinidine generally used to treat heart rhythm problems. colchicine used to treat gout. pravastatin and rosuvastatin used to treat high cholesterol levels. sulfasalazine used to treat rheumatoid arthritis. alfentanil used for anaesthesia in surgery; fentanyl used in pre-procedures as a pain reliever as well as an anaesthetic. cyclosporine, everolimus, tacrolimus, and sirolimus used in organ transplantation to prevent rejection. dihydroergotamine and ergotamine used to treat migraine. pimozide used to treat schizophrenia and chronic psychosis. the following medicines may reduce the effectiveness of ibrance: carbamazepine and phenytoin, used to stop seizures or fits. enzalutamide to treat prostate cancer. rifampin used to treat tuberculosis (tb). st. john's wort, an herbal product used to treat mild depression and anxiety. ibrance with food and drink avoid grapefruit and grapefruit juice while you are taking ibrance as it may increase the side effects of ibrance. pregnancy and breast-feeding and fertility you should not use ibrance if you are pregnant. you should avoid becoming pregnant while taking ibrance. discuss contraception with your doctor if there is any possibility that you or your partner may become pregnant. if you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine. women of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., double-barrier contraception such as condom and diaphragm). these methods should be used during therapy and for at least 3 weeks after completing therapy for females and for at least 14 weeks for males. breast-feeding you should not breast-feed while taking ibrance. it is not known if ibrance is excreted in breast milk. fertility palbociclib may decrease fertility in men. therefore, men may consider sperm preservation before taking ibrance. driving and using machines tiredness is a very common side effect. if you feel unusually tired, take 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{'Title': '3. how to take ibrance', 'Section_Content': 'always take this medicine exactly as your doctor or pharmacist has told you. check with your doctor or pharmacist if you are not sure. the recommended dose is 125 mg of ibrance taken once a day for 3 weeks followed by 1 week without taking ibrance. your doctor will tell you how many capsules of ibrance to take. if you experience certain side effects while you are taking ibrance (see section 4 "possible side effects"), your doctor may lower your dose or stop treatment, either temporarily or permanently. the dose may be lowered to one of the other available strengths 100 mg or 75 mg. take ibrance once a day at about the same time every day with food, preferably a meal. swallow the capsule whole with a glass of water. do not chew or crush the capsules. do not open the capsules. if you take more ibrance than you should if you have taken too much ibrance, see a doctor or go to a hospital immediately. urgent treatment may be necessary. take the carton and this leaflet, so that the doctor knows what you have been taking. if you forget to take ibrance if you miss a dose or vomit, take your next dose as scheduled. do not take a double dose to make up for the forgotten capsules. if you stop taking ibrance do not stop taking ibrance unless your doctor tells you to. if you have any further questions on the use of this medicine, ask your doctor or pharmacist.', 'Entity_Recognition': [{'Text': 'ibrance', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 12, 'EndOffset': 25}, {'Text': '125', 'Type': 'NUMBER', 'BeginOffset': 159, 'EndOffset': 162}, {'Id': 1, 'BeginOffset': 169, 'EndOffset': 176, 'Score': 0.8768466114997864, 'Text': 'ibrance', 'Category': 'MEDICATION', 'Type': 'BRAND_NAME', 'Traits': [], 'Attributes': [{'Type': 'DOSAGE', 'Score': 0.9945535659790039, 'RelationshipScore': 0.9998914003372192, 'RelationshipType': 'DOSAGE', 'Id': 0, 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{'Title': '4. possible side effects', 'Section_Content': 'like all medicines, this medicine can cause side effects, although not everybody gets them: contact your doctor immediately if you have any of these symptoms: fever, chills, weakness, shortness of breath, bleeding, or easy bruising which could be a sign of a serious blood disorder. difficulty breathing, dry cough or chest pain which could be a sign of inflammation of the lungs. other side effects with ibrance may include: very common side effects (may affect more than 1 in 10 people): infections reduction in white blood cells, red blood cells, and blood platelets feeling of tiredness decreased appetite inflammation of the mouth and lips (stomatitis), nausea, vomiting, diarrhoea rash hair loss weakness fever abnormalities in liver blood tests dry skin common side effects (may affect up to 1 in 10 people): fever with a drop in the white blood cell count (febrile neutropenia) blurred vision, increased tearing, dry eye alteration in taste (dysgeusia) nosebleed reporting of side effects if you get any side effects, talk to your doctor, pharmacist, or nurse. this includes any possible side effects not listed in this leaflet. you can also report side effects directly via the national reporting system listed in appendix v. by reporting side effects, you can help provide more information on the safety of this medicine.', 'Entity_Recognition': [{'Text': 'ibrance', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Text': 'all medicines', 'Type': 'TREATMENT', 'BeginOffset': 5, 'EndOffset': 18}, {'Text': 'this medicine', 'Type': 'TREATMENT', 'BeginOffset': 20, 'EndOffset': 33}, {'Id': 10, 'BeginOffset': 44, 'EndOffset': 56, 'Score': 0.9639590978622437, 'Text': 'side effects', 'Category': 'MEDICAL_CONDITION', 'Type': 'DX_NAME', 'Traits': [{'Name': 'SYMPTOM', 'Score': 0.8010591268539429}]}, {'Text': 'these symptoms', 'Type': 'PROBLEM', 'BeginOffset': 143, 'EndOffset': 157}, {'Id': 11, 'BeginOffset': 159, 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{'Title': '5. how to store ibrance', 'Section_Content': 'keep this medicine out of the sight and reach of children. do not use this medicine after the expiry date which is stated on the bottle or blister and carton after "exp". the expiry date refers to the last day of that month. this medicine does not require any special storage conditions. do not use this medicine if you notice that the pack is damaged or shows signs of tampering. do not throw away any medicines via wastewater or household waste. ask your pharmacist how to throw away medicines you no longer use. these measures will help protect the environment.', 'Entity_Recognition': None}
{'Title': '6. contents of the pack and other information', 'Section_Content': 'what ibrance contains - the active substance is palbociclib. ibrance hard capsules come in different strengths. - ibrance 75 mg hard capsule: each capsule contains 75 mg palbociclib. - ibrance 100 mg hard capsule: each capsule contains 100 mg palbociclib. - ibrance 125 mg hard capsule: each capsule contains 125 mg palbociclib. - the other ingredients are: capsule content: microcrystalline cellulose, lactose monohydrate, sodium starch glycolate type a, colloidal anhydrous silica, magnesium stearate. capsule shell: gelatin, red iron oxide (e172), yellow iron oxide (e172), titanium dioxide (e171). printing ink: shellac, titanium dioxide (e171), ammonium hydroxide (28% solution), propylene glycol, simeticone (see section 2 "ibrance contains lactose"). what ibrance looks like and contents of the pack - ibrance 75 mg is supplied as opaque, hard capsules, with a light orange body (printed "pbc 75" in white) and a light orange cap (printed "pfizer" in white). - ibrance 100 mg is supplied as opaque, hard capsules, with a light orange body (printed "pbc 100" in white) and a caramel cap (printed "pfizer" in white). - ibrance 125 mg is supplied as opaque, hard capsules, with a caramel body (printed "pbc 125" in white) and a caramel cap (printed "pfizer" in white). ibrance 75 mg, 100 mg, and 125 mg are available in blister packs of 21 or 63 hard capsules and in plastic bottles of 21 hard capsules. not all pack sizes may be marketed.', 'Entity_Recognition': [{'Text': 'ibrance', 'Type': 'PRODUCT_NAME', 'BeginOffset': 0, 'EndOffset': 0}, {'Id': 0, 'BeginOffset': 48, 'EndOffset': 59, 'Score': 0.9948893785476685, 'Text': 'palbociclib', 'Category': 'MEDICATION', 'Type': 'GENERIC_NAME', 'Traits': []}, {'Text': 'ibrance hard capsules', 'Type': 'TREATMENT', 'BeginOffset': 61, 'EndOffset': 82}, {'Id': 2, 'BeginOffset': 114, 'EndOffset': 121, 'Score': 0.9744570851325989, 'Text': 'ibrance', 'Category': 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