IBRANCE 75mg tablets medication leaflet

IBRANCE 75 mg film-coated tablets

IBRANCE 100 mg film-coated tablets

IBRANCE 125 mg film-coated tablets

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.

Film-coated tablet (tablet).

IBRANCE 75 mg film-coated tablets

Round, 10.3 mm, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC 75”on the other side.

IBRANCE 100 mg film-coated tablets

Oval, 15.0 x 8.0 mm, green, film-coated tablets debossed with “Pfizer” on one side and “PBC 100” onthe other side.

IBRANCE 125 mg film-coated tablets

Oval, 16.2 x 8.6 mm, light purple, film-coated tablets debossed with “Pfizer” on one side and “PBC125” on the other side.

IBRANCE is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growthfactor 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 (seesection 5.1).

In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizinghormone-releasing hormone (LHRH) agonist.

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

The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by7 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 untilunacceptable toxicity occurs.

When coadministered with palbociclib, the aromatase inhibitor should be administered according tothe dose schedule reported in the Summary of Product Characteristics. Treatment ofpre/perimenopausal women with the combination of palbociclib plus an aromatase inhibitor shouldalways be combined with an LHRH agonist (see section 4.4).

When coadministered with palbociclib, the recommended dose of fulvestrant is 500 mg administeredintramuscularly 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 ofpalbociclib plus fulvestrant, and throughout its duration, pre/perimenopausal women should be treatedwith LHRH agonists according to local clinical practice.

Patients should be encouraged to take their dose at approximately the same time each day. If thepatient vomits or misses a dose, an additional dose should not be taken that day. The next prescribeddose should be taken at the usual time.

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 dosereductions, or permanent discontinuation as per dose reduction schedules provided in Tables 1, 2, and3 (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 thebeginning 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, completeblood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of acycle and as clinically indicated.

Absolute neutrophil counts (ANC) of ≥ 1,000/mm3 and platelet counts of ≥ 50,000/mm3 arerecommended 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 completeblood 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 tocomplete cycle and repeat complete blood count on Day 22.

If Grade 4 on Day 22, see Grade 4 dose modification guidelinesbelow.

Consider dose reduction in cases of prolonged (> 1 week) recoveryfrom Grade 3 neutropenia or recurrent Grade 3 neutropenia on Day 1of subsequent cycles.

Grade 3 ANCb At any time:(< 1,000 to 500/mm3) Withhold IBRANCE until recovery to Grade ≤ 2+ Fever ≥ 38.5 ºC Resume at next lower dose.and/or infection

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 withclinical 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 Withhold until symptoms resolve to:persisting despite medical treatment) - Grade ≤ 1;

- Grade ≤ 2 (if not considered a safety riskfor the patient)

Resume at the next lower dose.

Grading according to CTCAE 4.0.

CTCAE=Common Terminology Criteria for Adverse Events.

IBRANCE should be permanently discontinued in patients with severe interstitial lung disease(ILD)/pneumonitis (see section 4.4).

No dose adjustment of IBRANCE is necessary in patients ≥ 65 years of age (see section 5.2).

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), therecommended dose of IBRANCE is 75 mg once daily on Schedule 3/1 (see sections 4.4 and 5.2).

No dose adjustment of IBRANCE is required for patients with mild, moderate or severe renalimpairment (creatinine clearance [CrCl] ≥ 15 mL/min). Insufficient data are available in patientsrequiring haemodialysis to provide any dose adjustment recommendation in this patient population(see sections 4.4 and 5.2).

There is no relevant use of IBRANCE in the paediatric population for the treatment of breastcarcinoma. The efficacy of IBRANCE in children and adolescents < 18 years of age has not beendemonstrated. Currently available data are described in sections 4.8, 5.1, and 5.2.

IBRANCE is for oral use. The tablets may be taken with or without food (see section 5.2). Palbociclibshould 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 toswallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Use of preparations containing St. John’s Wort (see section 4.5).

Pre/perimenopausal women

Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausalwomen are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanismof action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausalwomen 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).

Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patientswho develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see sections 4.2and 4.8).

Interstitial lung disease/pneumonitis

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with IBRANCEwhen taken in combination with endocrine therapy.

Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 1.4% of IBRANCE-treated patientshad 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 fatalitiesreported (see section 4.8).

Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia,cough, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected tohave developed ILD/pneumonitis, IBRANCE should be immediately interrupted and the patientshould be evaluated. IBRANCE should be permanently discontinued in patients with severe ILD orpneumonitis (see section 4.2).

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 randomisedclinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in anycombination (see section 4.8).

Patients should be monitored for signs and symptoms of infection and treated as medically appropriate(see section 4.2).

Physicians should inform patients to promptly report any episodes of fever.

Venous thromboembolic events were reported in patients treated with IBRANCE (see section 4.8).

Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonaryembolism, and treated as medically appropriate.

IBRANCE should be administered with caution to patients with moderate or severe hepaticimpairment, with close monitoring of signs of toxicity (see sections 4.2 and 5.2).

IBRANCE should be administered with caution to patients with moderate or severe renal impairment,with close monitoring of signs of toxicity (see sections 4.2 and 5.2).

Concomitant treatment with inhibitors or inducers of CYP3A4

Strong inhibitors of CYP3A4 may lead to increased toxicity (see section 4.5). Concomitant use ofstrong CYP3A inhibitors during treatment with palbociclib should be avoided. Coadministrationshould only be considered after careful evaluation of the potential benefits and risks. Ifcoadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mgonce daily. When the strong inhibitor is discontinued, the dose of IBRANCE should be increased(after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3Ainhibitor (see section 4.5).

Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently arisk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducersshould be avoided. No dose adjustments are required for coadministration of palbociclib withmoderate 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 ofcontraception while taking IBRANCE (see section 4.6).

Palbociclib is primarily metabolised by CYP3A and sulphotransferase (SULT) enzyme SULT2A1.

In vivo, palbociclib is a weak, time-dependent inhibitor of CYP3A.

Effects of other medicinal products on the pharmacokinetics of palbociclib

Effect of CYP3A inhibitors

Coadministration of multiple 200 mg doses of itraconazole with a single 125 mg palbociclib doseincreased 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 beavoided (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 dosedecreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mgpalbociclib 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 asingle 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 formoderate CYP3A inducers (see section 4.4).

Effect of acid reducing agents

Coadministration of multiple doses of the PPI rabeprazole with a single 125 mg IBRANCE tabletunder fasted conditions had no effect on the rate and extent of absorption of palbociclib whencompared 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 exposureis 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 steadystate. 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 midazolamalone.

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 theirexposure.

Drug-drug interaction between palbociclib and letrozole

Data from the drug-drug interaction (DDI) evaluation portion of a clinical study in patients with breastcancer showed that there was no drug interaction between palbociclib and letrozole when the2 medicinal products were coadministered.

Effect of tamoxifen on palbociclib exposure

Data from a DDI study in healthy male subjects indicated that palbociclib exposures were comparablewhen a single dose of palbociclib was coadministered with multiple doses of tamoxifen and whenpalbociclib 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 relevantdrug interaction between palbociclib and fulvestrant when the two medicinal products werecoadministered.

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 breastcancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib withmedicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine) or BCRP (e.g.,pravastatin, rosuvastatin, fluvastatin, sulfasalazine) may increase their therapeutic effect and adversereactions. Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationictransporter OCT1 and then may increase the exposure of medical product substrates of this transporter(e.g., metformin).

Drug-drug interaction between palbociclib and statins

Concomitant use of palbociclib with statins which are substrates of CYP3A4 and/or BCRP mayincrease the risk of rhabdomyolysis due to increased statin plasma concentration. Cases ofrhabdomyolysis including fatal cases have been reported following coadministration of palbociclibwith simvastatin or atorvastatin.

Females of childbearing potential who are receiving this medicinal product, or their male partnersshould use adequate contraceptive methods (e.g., double-barrier contraception) during therapy and forat least 3 weeks or 14 weeks after completing therapy for females and males, respectively (seesection 4.5).

There are no or limited amount of data from the use of palbociclib in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). IBRANCE is not recommended duringpregnancy and in women of childbearing potential not using contraception.

No studies have been conducted in humans or animals to assess the effect of palbociclib on milkproduction, its presence in breast milk, or its effects on the breast-fed child. It is unknown whetherpalbociclib is excreted in human milk. Patients receiving palbociclib should not breast-feed.

There were no effects on oestrous cycle (female rats) or mating and fertility in rats (male or female) innon-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, epididymalhypospermia, lower sperm motility and density, and decreased prostate secretion) in non-clinicalsafety studies, male fertility may be compromised by treatment with palbociclib (see section 5.3).

Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE.

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

The overall safety profile of IBRANCE is based on pooled data from 872 patients who receivedpalbociclib in combination with endocrine therapy (N=527 in combination with letrozole and N=345in combination with fulvestrant) in randomised clinical studies in HR-positive, HER2-negativeadvanced or metastatic breast cancer.

The most common (≥ 20%) adverse reactions of any grade reported in patients receiving palbociclib inrandomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis,anaemia, diarrhoea, alopecia and thrombocytopenia. The most common (≥ 2%) Grade ≥ 3 adversereactions 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 patientsreceiving 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.

Table 4 reports the adverse reactions from the pooled dataset of 3 randomised studies. The medianduration of palbociclib treatment across the pooled dataset at the time of the final OS analysis was14.8 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 categoriesare 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 decreasingseriousness.

Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872)and during post-marketing experience

System Organ Class All Grades Grade 3 Grade 4

Frequency n (%) n (%) n (%)

Preferred terma (PT)

Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872)and during post-marketing experience

System Organ Class All Grades Grade 3 Grade 4

Frequency n (%) n (%) n (%)

Preferred terma (PT)

Very common

Infectionsb 516 (59.2) 49 (5.6) 8 (0.9)

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)

Very common

Decreased appetite 152 (17.4) 8 (0.9) 0 (0.0)

Common

Dysgeusia 79 (9.1) 0 (0.0) 0 (0.0)

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)

Common

Venous thromboembolismj 28 (3.2) 11 (1.3) 7 (0.8)

Common

Epistaxis 77 (8.8) 0 (0.0) 0 (0.0)

ILD/pneumonitisi 12 (1.4) 1 (0.1) 0 (0.0)

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)

Very common

Rashh 158 (18.1) 7 (0.8) 0 (0.0)

Alopecia 234 (26.8) N/A N/A

Dry skin 93 (10.7) 0 (0.0) 0 (0.0)

Common

Palmar-plantar erythrodysaesthesia syndrome 16 (1.8) 0 (0.0) 0 (0.0)

Uncommon

Cutaneous lupus erythematosus 1 (0.1) 0 (0.0) 0 (0.0)

Erythema multiforme 1 (0.1) 0 (0.0) 0 (0.0)

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)

Very common

ALT increased 92 (10.6) 18 (2.1) 1 (0.1)

AST Increased 99 (11.4) 25 (2.9) 0 (0.0)

Common

Blood creatinine increased 57 (6.5) 3 (0.3) 2 (0.2)

ALT=alanine aminotransferase; AST=aspartate aminotransferase; ILD=interstitial lung disease; N/n=numberof patients; N/A=not applicable.

Table 4. Adverse reactions based on pooled dataset from 3 randomised studies (N=872)and during post-marketing experience

System Organ Class All Grades Grade 3 Grade 4

Frequency n (%) n (%) n (%)

Preferred terma (PT)a PTs are listed according to MedDRA 17.1.b Infections includes all PTs that are part of the System Organ Class Infections and infestations.c Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.d Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.e Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.f Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.g Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouthulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.h Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rashpapular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.i ILD/pneumonitis includes any reported PTs that are part of the Standardised MedDRA Query Interstitial

Lung Disease (narrow).j Venous thromboembolism includes the following PTs: pulmonary embolism, embolism, deep veinthrombosis, peripheral embolism, thrombosis.

Table 5. Laboratory abnormalities observed in pooled dataset from 3 randomised studies(N=872)

IBRANCE plus letrozole or Comparator arms*fulvestrant

Laboratory All Grade 3 Grade 4 All Grade 3 Grade 4abnormalities grades % % grades % %% %

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

Blood creatinine increased 95.5 1.6 0.3 86.8 0.0 0.0

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 ofpatients; N/A=not applicable.

Note: Laboratory results are graded according to the NCI CTCAE version 4.0 severity grade.

* letrozole or fulvestrant

Overall, neutropenia of any grade was reported in 716 (82.1%) patients receiving IBRANCEregardless 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 medianduration 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 withfulvestrant 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 overallclinical programme.

Palbociclib, in combination with chemotherapy, has been evaluated in 79 paediatric patients with solidtumours including r/r Ewing sarcoma (EWS) in study A5481092 (see section 5.1). The safety profileof palbociclib in this paediatric population was consistent with the known safety profile in the adultpopulation.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EF01.

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 cellularproliferation.

Through inhibition of CDK4/6, palbociclib reduced cellular proliferation by blocking progression ofthe cell from G1 into S phase of the cell cycle. Testing of palbociclib in a panel of molecularlyprofiled 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 withloss of palbociclib activity. However, in a follow-up study with fresh tumour samples, no relationbetween RB1 expression and tumour response was observed. Similarly, no relation was observedwhen studying the response to palbociclib in in vivo models with patient-derived xenografts (PDXmodels). Available clinical data are reported in the clinical efficacy and safety section (seesection 5.1).

The effect of palbociclib on the QT interval corrected for heart rate (QTc) interval was evaluated usingtime matched electrocardiogram (ECG) evaluating the change from baseline and correspondingpharmacokinetic data in 77 patients with advanced breast cancer. Palbociclib did not prolong the QTcto any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).

Randomised Phase 3 Study PALOMA-2: IBRANCE in combination with letrozole

The efficacy of palbociclib in combination with letrozole versus letrozole plus placebo was evaluatedin an international, randomised, double-blind, placebo-controlled, parallel-group, multicentre studyconducted in women with ER-positive, HER2-negative locally advanced breast cancer not amenableto resection or radiation therapy with curative intent or metastatic breast cancer who had not receivedprior systemic treatment for their advanced disease.

A total of 666 postmenopausal women were randomised 2:1 to the palbociclib plus letrozole arm orplacebo 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 metastaticversus  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 patientswith massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, andover 50% liver involvement), were not eligible for enrolment into the study.

Patients continued to receive assigned treatment until objective disease progression, symptomaticdeterioration, 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 thepalbociclib plus letrozole arm and the placebo plus letrozole arm. The median age of patients enrolledin this study was 62 years (range 28-89), 48.3% of patients had received chemotherapy and 56.3% hadreceived antihormonal therapy in the (neo)adjuvant setting prior to their diagnosis of advanced breastcancer 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-onlydisease, 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 ofpalbociclib plus letrozole, with a stratified log-rank test 1-sided p-value of < 0.000001. An updatedanalysis of the primary and secondary endpoints was performed after an additional 15 months offollow 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 andupdated cutoff dates

Primary analysis Updated analysis(26 February 2016 cutoff) (31 May 2017 cutoff)

IBRANCE Placebo IBRANCE Placeboplus letrozole plus letrozole plus letrozole plus letrozole(N = 444) (N = 222) (N = 444) (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 24.8 (22.1, NE) 14.5 (12.9, 17.1) 27.6 (22.4, 30.3) 14.5 (12.3, 17.1)(95% CI)]

Hazard ratio [(95% CI) 0.576 (0.463, 0.718), p< 0.000001 0.563 (0.461, 0.687), p< 0.000001and p-value]

Progression-free survival by independent assessment

Number of events (%) 152 (34.2) 96 (43.2) 193 (43.5) 118 (53.2)

Median PFS [months 30.5 (27.4, NE) 19.3 (16.4, 30.6) 35.7 (27.7, 38.9) 19.5 (16.6, 26.6)(95% CI)]

Hazard ratio (95% CI) 0.653 (0.505, 0.844), p=0.000532 0.611 (0.485, 0.769), p=0.000012and 1-sided p-value

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 60.7 (55.2, 65.9) 49.1 (41.4, 56.9) 62.4 (57.0, 67.6) 49.7 (42.0, 57.4)[% (95% CI)]

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 benefitresponse; 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)100 palbociclib+letrozole90 placebo+letrozole0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Time (Month)

Number of patients at risk

PAL+LET 444 394 359 327 294 262 239 221 204 192 164 146 83 26 5 2 0

PBO+LET 222 170 147 129 114 97 80 73 61 55 45 37 26 5 2 2 2

PAL=palbociclib; LET=letrozole; PBO=placebo.

A series of prespecified subgroup PFS analyses was performed based on prognostic factors andbaseline characteristics to investigate the internal consistency of treatment effect. A reduction in the

Progression-Free Survival Probability (%)risk of disease progression or death in favour of the palbociclib plus letrozole arm was observed in allindividual patient subgroups defined by stratification factors and baseline characteristics in theprimary and in the updated analysis.

Based on the 31-May-2017 data cutoff date, this reduction in risk continued to be observed in thefollowing 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 visceralmetastases (HR of 0.50 [95% CI: 0.37, 0.67], mPFS 35.9 months versus 17.0 months) and (2) patientswith either bone only disease (HR of 0.41 [95% CI: 0.26, 0.63], mPFS 36.2 months versus11.2 months) or without bone-only disease (HR of 0.62 [95% CI: 0.50, 0.78], mPFS 24.2 monthsversus 14.5 months). Similarly, a reduction in the risk of disease progression or death in thepalbociclib plus letrozole arm was observed in 512 patients whose tumour tested positive for Rbprotein expression by immunohistochemistry (IHC) (HR of 0.543 [95% CI: 0.433, 0.681], mPFS27.4 months versus 13.7 months). For the 51 patients IHC negative for Rb expression, the differencebetween treatment arms was not statistically significant (HR of 0.868 [95% CI: 0.424, 1.777], mPFS23.2 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 patientswith 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-2study (intent-to-treat population; 31-May-2017 cutoff date)

Visceral disease Non-visceral disease

IBRANCE Placebo IBRANCE Placeboplus letrozole plus letrozole plus letrozole plus letrozole(N=214) (N=110) (N=230) (N=112)

OR [% (95% CI)] 59.8 46.4 36.1 31.3(52.9, 66.4) (36.8, 56.1) (29.9, 42.7) (22.8, 40.7)

TTR, Median [months 5.4 5.3 3.0 5.5(range)] (2.0, 30.4) (2.6, 27.9) (2.1, 27.8) (2.6, 22.2)

N=number of patients; CI=confidence interval; OR=objective response based on confirmed and unconfirmedresponses 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 therapywas 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).

The results from the final OS analysis from the PALOMA-2 study are presented in Table 8. After amedian follow-up time of 90 months, the final OS results were not statistically significant. The

Kaplan-Meier plot of OS is shown in Figure 2.

Table 8. PALOMA-2 (intent-to-treat population) - Final overall survival results

Final Overall Survival (OS)(15 November 2021 Cutoff)

IBRANCE Placeboplus letrozole plus letrozole(N=444) (N=222)

Number of events (%) 273 (61.5) 132 (59.5)

Number of subjects remaining112 (25.2) 43 (19.4)in follow-up (%)

Median OS (months [95% CI]) 53.9 (49.8, 60.8) 51.2 (43.7, 58.9)

Hazard ratio (95% CI) and0.956 (0.777, 1.177), p=0.6755†*p-value†

CI=confidence interval.

* Not statistically significant.

† 2-sided p-value from the log-rank test stratified by disease site (visceral vs. non-visceral) per randomisation.

Figure 2. Kaplan-Meier plot of overall survival (intent-to-treat population) - PALOMA-2100 palbociclib+letrozole90 placebo+letrozole0 12 24 36 48 60 72 84 96 108

Time (Month)

Number of patients at risk

PAL+LET 444 400 325 280 222 174 145 128 13 0

PBO+LET 222 203 168 126 95 72 60 53 4 0

PAL=palbociclib; LET=letrozole; PBO=placebo.

Randomised Phase 3 Study PALOMA-3: IBRANCE in combination with fulvestrant

The efficacy of palbociclib in combination with fulvestrant versus fulvestrant plus placebo wasevaluated in an international, randomised, double-blind, parallel-group, multicentre study conducted inwomen with HR-positive, HER2-negative locally advanced breast cancer not amenable to resection orradiation therapy with curative intent or metastatic breast cancer, regardless of their menopausalstatus, whose disease progressed after prior endocrine therapy in the (neo)adjuvant or metastaticsetting.

A total of 521 pre/peri- and postmenopausal women who had progressed on or within 12 months fromcompletion of adjuvant endocrine therapy or on or within 1 month from prior endocrine therapy foradvanced disease, were randomised 2:1 to palbociclib plus fulvestrant or placebo plus fulvestrant andstratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry(pre/peri- versus postmenopausal), and presence of visceral metastases. Pre/perimenopausal womenreceived the LHRH agonist goserelin. Patients with advanced/metastatic, symptomatic, visceralspread, that were at risk of life-threatening complications in the short term (including patients withmassive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over50% liver involvement), were not eligible for enrolment into the study.

Patients continued to receive assigned treatment until objective disease progression, symptomaticdeterioration, 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 thepalbociclib plus fulvestrant arm and the placebo plus fulvestrant arm. The median age of patientsenrolled 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 systemictherapy and most patients in each treatment arm had received a previous chemotherapy regimen for

Overall Survival Probability (%)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. Secondaryendpoints included OR, CBR, OS, safety, and time-to-deterioration (TTD) in pain endpoint.

The study met its primary endpoint of prolonging investigator-assessed PFS at the interim analysisconducted on 82% of the planned PFS events; the results crossed the prespecified Haybittle-Petoefficacy boundary (α=0.00135), demonstrating a statistically significant prolongation in PFS and aclinically meaningful treatment effect.

A more mature update of efficacy data is reported in Table 9.

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 fulvestrantarm compared with the placebo plus fulvestrant arm was observed; this result was not statisticallysignificant at the prespecified significance level of 0.0235 (1-sided). In the placebo plus fulvestrantarm, 15.5% of randomised patients received palbociclib and other CDK inhibitors as post progressionsubsequent treatments.

The results from the investigator-assessed PFS and final OS data from PALOMA-3 study arepresented in Table 9. The relevant Kaplan-Meier plots are shown in Figures 3 and 4, respectively.

Table 9. Efficacy results - PALOMA-3 study (investigator assessment, intent-to-treatpopulation)

Updated analysis(23 October 2015 cutoff)

IBRANCE Placeboplus fulvestrant plus fulvestrant(N=347) (N=174)

Progression-free survival (PFS)

Number of events (%) 200 (57.6) 133 (76.4)

Median [months (95% CI)] 11.2 (9.5, 12.9) 4.6 (3.5, 5.6)

Hazard ratio (95% CI) and p-value 0.497 (0.398, 0.620), p< 0.000001

Secondary efficacy endpoints

OR [% (95% CI)] 26.2 (21.7, 31.2) 13.8 (9.0, 19.8)

OR (measurable disease) [% (95% CI)] 33.7 (28.1, 39.7) 17.4 (11.5, 24.8)

CBR [% (95% CI)] 68.0 (62.8, 72.9) 39.7 (32.3, 47.3)

Final overall survival (OS)(13 April 2018 cutoff)

Number of events (%) 201 (57.9) 109 (62.6)

Median [months (95% CI)] 34.9 (28.8, 40.0) 28.0 (23.6, 34.6)

Hazard ratio (95% CI) and p-value† 0.814 (0.644, 1.029)p=0.0429†*

CBR=clinical benefit response; CI=confidence interval; N=number of patients; OR=objective response.

Secondary endpoint results are based on confirmed and unconfirmed responses according to RECIST 1.1.

* Not statistically significant.† 1-sided p-value from the log-rank test stratified by the presence of visceral metastases and sensitivity to priorendocrine therapy per randomisation.

Figure 3. Kaplan-Meier plot of progression-free survival (investigator assessment,intent-to-treat population) - PALOMA-3 study (23 October 2015 cutoff)100 palbociclib+fulvestrant90 placebo+fulvestrant0 2 4 6 8 10 12 14 16 18 20 22

Time (Month)

Number of patients at risk

PAL+FUL 347 276 245 215 189 168 137 69 38 12 2 1

PBO+FUL 174 112 83 62 51 43 29 15 11 4 1 0

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

A reduction in the risk of disease progression or death in the palbociclib plus fulvestrant arm wasobserved in all individual patient subgroups defined by stratification factors and baselinecharacteristics. 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 ofmetastatic disease (HR of 0.50 [95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of0.48 [95% CI: 0.33, 0.71]). Benefit was also observed regardless of lines of prior therapy in themetastatic 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 4. Kaplan-Meier plot of overall survival (intent-to-treat population) - PALOMA-3study (13 April 2018 cutoff)100 palbociclib+fulvestrant90 placebo+fulvestrant0 6 12 18 24 30 36 42 48 54

Time (Month)

Number of patients at risk

PAL+FUL 347 321 286 247 209 165 148 126 17 0

PBO+FUL 174 155 135 115 86 68 57 43 7 0

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

Progression-Free Survival Probability (%)

Overall Survival Probability (%)

Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or withoutvisceral disease are displayed in Table 10.

Table 10. Efficacy results in visceral and non-visceral disease from PALOMA-3 study(intent-to-treat population)

Visceral disease Non-visceral disease

IBRANCE Placebo IBRANCE Placeboplus plus plus plusfulvestrant fulvestrant fulvestrant fulvestrant(N=206) (N=105) (N=141) (N=69)

OR [%, (95% CI)] 35.0 13.3 13.5 14.5(28.5, 41.9) (7.5, 21.4) (8.3, 20.2) (7.2, 25.0)

TTR, Median [months 3.8 5.4 3.7 3.6(range)] (3.5, 16.7) (3.5, 16.7) (1.9, 13.7) (3.4, 3.7)

N=number of patients; CI=confidence interval; OR= objective response based on confirmed and unconfirmedresponses 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 patientsin 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 pointsincrease from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in asymptom benefit by significantly delaying time-to-deterioration in pain symptom compared withplacebo plus fulvestrant (median 8.0 months versus 2.8 months; HR of 0.64 [95% CI: 0.49, 0.85];p< 0.001).

An open-label, randomised Phase 2 portion of study A5481092 compared the efficacy of thecombination of palbociclib with irinotecan (IRN) and temozolomide (TMZ) versus IRN and TMZalone in the treatment of paediatric (2 to <18 years of age) and young adults (18 to 20 years of age)with r/r EWS for whom no standard therapy is available.

The prespecified interim analysis was performed based on 33 event free survival (EFS) events (61.1%of 54 participants). The observed HR for palbociclib + IRN + TMZ compared to IRN + TMZ alonewas 2.03 (95% CI: 0.902, 4.572; stratified 1-sided p-value=0.9621).

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 (seesection 4.2 for information on paediatric use).

The pharmacokinetics of palbociclib were characterised in patients with solid tumours includingadvanced breast cancer and in healthy volunteers.

The Cmax of palbociclib is generally observed between 4 to 12 hours (time to reach maximumconcentration [Tmax]) following oral administration of IBRANCE tablets. The mean absolutebioavailability of palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to225 mg, the area under the curve (AUC) and Cmax increase proportionally with dose in general. Steadystate was achieved within 8 days following repeated once daily dosing. With repeated once dailyadministration, palbociclib accumulates with a median accumulation ratio of 2.4 (range 1.5-4.2).

The AUCinf and Cmax of palbociclib increased by 22% and 26%, respectively, when IBRANCE tabletswere given with a high-fat, high-calorie meal (approximately 800 to 1,000 calories with 150, 250, and500 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 fastedconditions. Based on these results, palbociclib tablets may be taken with or without food.

Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentrationdependence. The mean fraction unbound (fu) of palbociclib in human plasma in vivo increasedincrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib fuin human plasma in vivo with worsening renal function. In vitro, the uptake of palbociclib into humanhepatocytes occurred mainly via passive diffusion. Palbociclib is not a substrate of OATP1B1 or

OATP1B3.

In vitro and in vivo studies indicate that palbociclib undergoes extensive hepatic metabolism inhumans. Following oral administration of a single 125 mg dose of [14C]palbociclib to humans, themajor primary metabolic pathways for palbociclib involved oxidation and sulphonation, with acylationand glucuronidation contributing as minor pathways. Palbociclib was the major circulatingdrug-derived entity in plasma.

The majority of the material was excreted as metabolites. In faeces, the sulfamic acid conjugate ofpalbociclib 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 recombinantsulphotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in themetabolism of palbociclib.

The geometric mean apparent oral clearance (CL/F) of palbociclib was 63 L/h, and the mean plasmaelimination half-life was 28.8 hours in patients with advanced breast cancer. In 6 healthy male subjectsgiven a single oral dose of [14C]palbociclib, a median of 92% of the total administered radioactivedose was recovered in 15 days; faeces (74% of dose) was the major route of excretion, with 17% ofthe dose recovered in urine. Excretion of unchanged palbociclib in faeces and urine was 2% and 7% ofthe administered dose, respectively.

In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, and 2D6, and is not aninducer 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 aniontransporter (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.

Age, gender, and body weight

Based on a population pharmacokinetic analysis in 183 patients with cancer (50 male and 133 femalepatients, age ranging from 22 to 89 years, and body weight ranging from 38 to 123 kg), gender had noeffect on the exposure of palbociclib, and age and body weight had no clinically important effect onthe exposure of palbociclib.

Palbociclib exposure in children, adolescents and young adults with r/r solid tumours was similaracross the age groups (≤ 6 years old, > 6 to < 12 years old, ≥ 12 to < 18 years old, and ≥ 18 years old)over the dose range of 55-95 mg/m2 (BSA-normalised palbociclib dosing) administered orally oncedaily on Days 1 to 14 followed by 7 days off. Palbociclib steady state exposure at the 75 mg/m2 oncedaily dose in the paediatric population was similar to that observed in adult participants at theapproved 125 mg once daily dose (administered on Day 1 to Day 21 followed by 7 days off).

Data from a pharmacokinetic study in subjects with varying degrees of hepatic function indicate thatpalbociclib unbound exposure (unbound AUCinf) decreased by 17% in subjects with mild hepaticimpairment (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 tosubjects with normal hepatic function. Peak palbociclib unbound exposure (unbound Cmax) wasincreased 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 pharmacokineticanalysis that included 183 patients with advanced cancer, where 40 patients had mild hepaticimpairment 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 × ULNand any AST), mild hepatic impairment had no effect on the pharmacokinetics of palbociclib.

Data from a pharmacokinetic study in subjects with varying degrees of renal function indicate thattotal 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%, and15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normalrenal function. In addition, based on a population pharmacokinetic analysis that included 183 patientswith advanced cancer, where 73 patients had mild renal impairment and 29 patients had moderaterenal impairment, mild and moderate renal impairment had no effect on the pharmacokinetics ofpalbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiringhaemodialysis.

In a pharmacokinetic study in healthy volunteers, palbociclib AUCinf and Cmax values were 30% and35% higher, respectively, in Japanese subjects compared with non-Asian subjects after a single oraldose. 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 cumulativepharmacokinetic, safety, and efficacy data across Asian and non-Asian populations, no doseadjustment based on Asian race is considered necessary.

The primary target organ findings following single and/or repeat dosing includedhaematolymphopoietic and male reproductive organ effects in rats and dogs, and effects on bone andactively growing incisors in rats only. These systemic toxicities were generally observed at clinicallyrelevant exposures based on AUC. Partial to full reversal of effects on the hematolymphopoietic, malereproductive systems, and incisor teeth were established, whereas the bone effect was not reversedfollowing a 12-week nondosing period. In addition, cardiovascular effects (QTc prolongation,decreased heart rate, and increased RR interval and systolic blood pressure) were identified intelemetered dogs at ≥ 4 times human clinical exposure based on Cmax.

Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year ratstudy. 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 celltumours in the central nervous system of males at 30 mg/kg/day; there were no neoplastic findings infemale rats at any dose up to 200 mg/kg/day. The NOEL for palbociclib-related carcinogenicity effectswas 10 mg/kg/day (approximately 2 times the human clinical exposure based on AUC) and200 mg/kg/day (approximately 4 times the human clinical exposure based on AUC) in males andfemales, respectively. The relevance of the male rat neoplastic finding to humans is unknown.

Palbociclib was not mutagenic in a bacterial reverse mutation (Ames) assay and did not inducestructural chromosomal aberrations in the in vitro human lymphocyte chromosome aberration assay.

Palbociclib induced micronuclei via an aneugenic mechanism in Chinese Hamster Ovary cells in vitroand in the bone marrow of male rats at doses ≥ 100 mg/kg/day. The exposure of animals at the noobserved effect level for aneugenicity was approximately 7 times human clinical exposure based on

AUC.

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 wereobserved in female reproductive tissues in repeat-dose toxicity studies up to 300 mg/kg/day in the ratand 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 malehumans 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 tohuman clinical exposure based on AUC, respectively. Partial reversibility of male reproductive organeffects 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 malerats 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 inregulating 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 observedin rats. Reduced foetal body weights were observed at a maternally toxic dose of 300 mg/kg/day inrats (3 times human clinical exposure based on AUC), and an increased incidence of skeletalvariations, including small phalanges in the forelimb was observed at a maternally toxic dose of20 mg/kg/day in rabbits (4 times human clinical exposure based on AUC). Actual foetal exposure andcross-placenta transfer have not been examined.

Microcrystalline cellulose

Colloidal silicon dioxide

Crospovidone

Magnesium stearate

Succinic acid

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)

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original blister package in order to protect from moisture.

PVC/OPA/Al/PVC/Al blister card containing 7 film-coated tablets (1 film-coated tablet per cell). Eachcarton contains 21 film-coated tablets (3 blister cards per carton) or 63 film-coated tablets (9 blistercards per carton).

PVC/OPA/Al/PVC/Al blister card containing 7 film-coated tablets (1 film-coated tablet per cell) in awallet card. Each carton contains 21 film-coated tablets (3 wallet cards per carton).

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

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)

EU/1/16/1147/016 (21 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)

EU/1/16/1147/017 (21 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)

EU/1/16/1147/018 (21 film-coated tablets in carton)

Date of first authorisation: 09 November 2016

Date of latest renewal: 16 July 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.