ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

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.

• 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.

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/mm3and 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 °C 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).

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.

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).

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.

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).

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

• < 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 Neutropenia0	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	77 (8.8)	0 (0.0)	0 (0.0)
ILD/pneumonitis ,i	12(1.4)	1 (0.1)	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.

Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872)

System organ class	All Grades	Grade 3	Grade 4
Frequency Preferred terma	n (%)	n (%)	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.

• 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 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.

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)

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.

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 efficacy boundary (a=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=0.0429r

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.

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)

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

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 po	pulation)
	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 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.

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 x 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.

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

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

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.

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 × 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 × 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.

• 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/mm3and 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 3 a	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 °C 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).

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 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.

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.

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.

• 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 Infections'5	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)

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	77 (8.8)	0 (0.0)	0 (0.0)
ILD/pneumonitis ,i	12(1.4)	1 (0.1)	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).

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.

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 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.

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)

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.

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 efficacy boundary (a=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=0.0429r

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.

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)

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

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 po	pulation)
	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.

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, relative to subjects with normal hepatic function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer, where 40 patients had mild hepatic impairment based on National Cancer Institute (NCI) classification (total bilirubin < Upper Limit of Normal (ULN) and Aspartate Aminotransferase (AST) > ULN, or total bilirubin > 1.0 to 1.5 x ULN and any AST), mild hepatic impairment had no effect on the pharmacokinetics 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.

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

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)

• 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.

• 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

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Pfizer Manufacturing Deutschland GmbH

Betriebsstatte 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.

ANNEX III

LABELLING AND PACKAGE LEAFLET

A. LABELLING

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

• 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:

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

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

• 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:

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

• 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:

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

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

• 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:

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

• 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:

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

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

• 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:

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.

• 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:

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

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.

• 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:

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

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.

• 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:

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

B. PACKAGE LEAFLET

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.

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 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.

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.

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

Betriebsstatte Freiburg

Mooswaldallee 1

79090 Freiburg

Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgique / Belgie /Belgien Pfizer S.A. / N.V. Tel/Tel: +32 (0)2 554 62 11	Lietuva Pfizer Luxembourg SARL filialas Lietuvoje Tel. + 370 52 51 4000
BtnrapuH n<|)aH3ep ^KKceM6ypr C’AP^, K.toh Btnrapua Ten.: +359 2 970 4333	Luxembourg/Lu­xemburg Pfizer S.A. Tel/Tel: +32 (0)2 554 62 11
Ceska republika Pfizer PFE, spol. s r.o. Tel.: +420–283–004–111	Magyarorszag 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
EZZ6.6a Pfizer Ez.z.ac A.E. Tql: +30 210 6785 800	Osterreich Pfizer Corporation Austria Ges.m.b.H. Tel: +43 (0)1 521 15–0
Espana Pfizer, S.L. Tel: +34 91 490 99 00	Polska Pfizer Polska Sp. z o.o. Tel.:+48 22 335 61 00
France Pfizer Tel: +33 (0)1 58 07 34 40	Portugal Pfizer Biofarmaceutica, Sociedade Unipessoal Lda Tel: +351 21 423 5500
Hrvatska Pfizer Croatia d.o.o. Tel: + 385 1 3908 777	Romania 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, podruznica za svetovanje s podrocja farmacevtske dejavnosti, Ljubljana Tel.: + 386 (0)1 52 11 400
^sland Icepharma hf. Simi: +354 540 8000	Slovenska republika Pfizer Luxembourg SARL, organizacna zlozka 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

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

^FTiis 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.

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 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.

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.

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 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

Betriebsstatte Freiburg

Mooswaldallee 1

79090 Freiburg

Germany

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

Belgique / Belgie /Belgien Pfizer S.A. / N.V. Tel/Tel: +32 (0)2 554 62 11	Lietuva Pfizer Luxembourg SARL filialas Lietuvoje Tel. + 370 52 51 4000
BtnrapuH n<|)aH3ep ^KKceM6ypr C’AP^, K.toh Btnrapua Ten.: +359 2 970 4333	Luxembourg/Lu­xemburg Pfizer S.A. Tel/Tel: +32 (0)2 554 62 11
Ceska republika Pfizer PFE, spol. s r.o. Tel.: +420–283–004–111	Magyarorszag 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
EZZ6.6a Pfizer Ez.z.ac A.E. Tql: +30 210 6785 800	Osterreich Pfizer Corporation Austria Ges.m.b.H. Tel: +43 (0)1 521 15–0
Espana Pfizer, S.L. Tel: +34 91 490 99 00	Polska Pfizer Polska Sp. z o.o. Tel.:+48 22 335 61 00
France Pfizer Tel: +33 (0)1 58 07 34 40	Portugal Pfizer Biofarmaceutica, Sociedade Unipessoal Lda Tel: +351 21 423 5500
Hrvatska Pfizer Croatia d.o.o. Tel: + 385 1 3908 777	Romania 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, podruznica za svetovanje s podrocja farmacevtske dejavnosti, Ljubljana Tel.: + 386 (0)1 52 11 400
^sland Icepharma hf. Simi: +354 540 8000	Slovenska republika Pfizer Luxembourg SARL, organizacna zlozka 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

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

^FTiis 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.

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 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.

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.

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.