Ibrance 75mg capsules

United Kingdom - English - MHRA (Medicines & Healthcare Products Regulatory Agency)

Buy It Now

Active ingredient:
Palbociclib
Available from:
Pfizer Ltd
ATC code:
L01XE33
INN (International Name):
Palbociclib
Dosage:
75mg
Pharmaceutical form:
Capsule
Administration route:
Oral
Class:
No Controlled Drug Status
Prescription type:
Valid as a prescribable product
Product summary:
BNF: 08010500; GTIN: 5013457013429

Read the complete document

Page 1 of 6

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

What IBRANCE is and what it is used for

What you need to know before you take IBRANCE

How to take IBRANCE

Possible side effects

How to store IBRANCE

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

Page 2 of 6

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).

Children and adolescents

IBRANCE is not to be used in children or adolescents (aged 18 years or under).

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.

Alfetanil used for anaesthesia in surgery; fentanyl used in pre-procedures as a pain reliever as

well as an anaesthetic.

Ciclosporin, 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, a 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.

Page 3 of 6

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.

Page 4 of 6

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.

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

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

Abnormalities in liver blood tests

Alteration in taste (dysgeusia)

Nosebleed

Dry skin

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 (see details below). By

reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom

Yellow Card Scheme website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the

Google Play or Apple App Store

Ireland

HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 676 4971; Fax: +353 1 676

2517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

Page 5 of 6

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

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 Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

Manufacturer

Page 6 of 6

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:

Ireland

Pfizer Healthcare Ireland

Tel: 1800 633 363 (toll free)

+44 (0)1304 616161

Malta

V.J. Salomone Pharma Ltd.

Tel. +356 21220174

United Kingdom

Pfizer Limited

Tel: +44 (0) 1304 616161

This leaflet was last revised in 02/2018

Detailed information on this medicine is available on the European Medicines Agency web site:

http://www.ema.europa.eu.

Ref: IB 6_0

Read the complete document

Object 1

IBRANCE 75 mg hard capsules

Summary of Product Characteristics Updated 08-Feb-2018 | Pfizer Limited

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 recommended dose of letrozole is 2.5 mg taken orally once

daily continuously throughout the 28-day cycle. Please refer to the Summary of Product Characteristics of

letrozole. Treatment of pre/perimenopausal women with the combination of palbociclib plus letrozole

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 ≥1000/mm

and platelet counts of ≥50,000/mm

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

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 ANC

(<1000 to 500/mm

Fever ≥38.5 °C and/or

At any time:

Withhold IBRANCE until recovery to Grade ≤2

infection

Resume at next lower dose.

Grade 4

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.

Table applies to all haematological adverse reactions except lymphopenia (unless associated with clinical

events, e.g., opportunistic infections).

ANC: Grade 1: ANC < LLN - 1500/mm

; Grade 2: ANC 1000 - <1500/mm

; Grade 3: ANC 500 -

<1000/mm

; Grade 4: ANC <500/mm

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.

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).

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 (AUC

) and the peak concentration (C

) 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 AUC

and C

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 AUC

and C

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 C

41%, but had limited impact on AUC

(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 AUC

and C

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 AUC

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

nonclinical 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,

alopecia, and diarrhoea. The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were

neutropenia, leukopenia, anaemia, fatigue, and infections.

Dose reductions or dose modifications due to any adverse reaction occurred in 34.4% of patients

receiving IBRANCE in randomised clinical studies regardless of the combination.

Permanent discontinuation due to an adverse reaction occurred in 4.1% 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 was 12.7 months.

Table 5 reports the laboratory abnormalities observed in pooled datasets from 3 randomized 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).

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

System Organ Class

Frequency

Preferred Term

All Grades

n (%)

Grade 3

n (%)

Grade 4

n (%)

Infections and infestations

Very common

Infections

477 (54.7)

39 (4.5)

6 (0.7)

Blood and lymphatic system disorders

Very common

Neutropenia

703 (80.6)

482 (55.3)

88 (10.1)

Leukopenia

394 (45.2)

228 (26.1)

5 (0.6)

Anaemia

241 (27.6)

38 (4.4)

2(0.2)

Thrombocytopenia

166 (19.0)

14 (1.6)

3 (0.3)

Common

Febrile neutropenia

14 (1.6)

10 (1.1)

1 (0.1)

Metabolism and nutrition disorders

Very common

Decreased appetite

138 (15.8 )

7(0.8)

0 (0.0)

Nervous system disorders

Common

Dysgeusia

74 (8.5)

0 (0.0)

0 (0.0)

Eye disorders

Common

Vision blurred

38 (4.4)

1 (0.1)

0 (0.0)

Lacrimation increased

50 (5.7)

0 (0.0)

0 (0.0)

Dry eye

31 (3.6)

0 (0.0)

0 (0.0)

Respiratory, thoracic and mediastinal disorders

Common

Epistaxis

73 (8.4)

0 (0.0)

0 (0.0)

Gastrointestinal disorders

Very common

Stomatitis

252 (28.9)

6 (0.7)

0 (0.0)

Nausea

298 (34.2)

3 (0.3)

0 (0.0)

Diarrhoea

214 (24.5)

9 (1.0)

0 (0.0)

Vomiting

149 (17.1)

4 (0.5)

0 (0.0)

Skin and subcutaneous tissue disorders

Very common

Rash

144 (16.5)

6 (0.7)

0 (0.0)

Alopecia

226 (25.9)

Common

Dry skin

82 (9.4)

0 (0.0)

0 (0.0)

General disorders and administration site conditions

Very common

Fatigue

342 (39.2)

20 (2.3)

2 (0.2)

Asthenia

112 (12.8)

12 (1.4)

0 (0.0)

Pyrexia

108(12.4)

1 (0.1)

0 (0.0)

Investigations

Common

ALT increased

70 (8.0)

15 (1.7)

1 (0.1)

AST Increased

75 (8.6)

22 (2.5)

0 (0.0)

ALT=alanine aminotransferase; AST=aspartate aminotransferase; N/n=number of patients; N/A=not

applicable.

Preferred Terms (PTs) are listed according to MedDRA 17.1.

Infections includes all PTs that are part of the System Organ Class Infections and infestations.

Neutropenia includes the following PTs: Neutropenia, Neutrophil count decreased.

Leukopenia includes the following PTs: Leukopenia, White blood cell count decreased.

Anaemia includes the following PTs: Anaemia, Haemoglobin decreased, Haematocrit decreased.

Thrombocytopenia includes the following PTs: Thrombocytopenia, Platelet count decreased.

Stomatitis includes the following PTs: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth

ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis.

Rash includes the following PTs: Rash, Rash maculo-papular, Rash pruritic, Rash erythematous, Rash

papular, Dermatitis, Dermatitis acneiform, Toxic skin eruption.

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

97.2

39.6

25.5

Neutrophils decreased

95.5

55.9

10.4

17.2

Anaemia

78.6

40.5

Platelets decreased

62.6

12.7

AST increased

48.4

40.8

ALT increased

40.8

31.1

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 703 (80.6%) patients receiving IBRANCE regardless of

the combination, with Grade 3 neutropenia being reported in 482 (55.3%) patients, and Grade 4

neutropenia being reported in 88 (10.1 %) 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% patients receiving IBRANCE in combination with

fulvestrant and in 2.1% 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 Yellow Card Scheme at:

www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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. Available clinical data are reported in the clinical efficacy and safety section (see section 5.1).

Mechanistic analyses revealed that the combination of palbociclib with antioestrogen agents enhanced the

reactivation of Rb through inhibition of Rb phosphorylation resulting in reduced E2F signalling and

growth arrest. In vivo studies using a patient-derived ER-positive breast cancer xenograft model (HBCx-

34) demonstrated that the combination of palbociclib and letrozole further enhanced inhibition of Rb

phosphorylation, downstream signalling and dose-dependent tumour growth. Studies are ongoing

investigating the importance of Rb expression for the activity of palbociclib in fresh tumour samples.

Cardiac electrophysiology

The effect of palbociclib on the QT interval corrected for heart rate (QTc) interval was evaluated using

time matched electrocardiogram (ECG) evaluating the change from baseline and corresponding

pharmacokinetic data in 77 patients with advanced breast cancer. Palbociclib did not prolong the QTc to

any clinically relevant extent at the recommended dose of 125 mg daily (Schedule 3/1).

Clinical 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 Tumors (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).

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. The median PFS for patients in the palbociclib plus letrozole arm was 24.8

months (95% CI: 22.1, NE) and 14.5 months (95% CI: 12.9, 17.1) for patients in the placebo plus

letrozole arm.

Efficacy data from PALOMA-2 study are summarised in Table 6 and the Kaplan-Meier curve for PFS is

shown in Figure 1.

Table 6. Efficacy results from PALOMA 2 study (intent-to-treat population)

26 February 2016 Cutoff

IBRANCE plus

letrozole

(N=444)

Placebo plus letrozole

(N=222)

Progression-free survival

Investigator assessment, Number of events (%)

194 (43.7%)

137 (61.7%)

Median [months (95% CI)

24.8 (22.1, NE)

14.5 (12.9, 17.1)

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

0.576 (0.46, 0.72), p<0.000001

Independent radiographic review, Number of events

152 (34.2%)

96 (43.2%)

Median [months (95% CI)

30.5 (27.4, NE)

19.3 (16.4, 30.6)

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

0.653 (0.505, 0.84), p=0.000532

Secondary efficacy endpoints (Investigator assessment)

OR [% (95% CI)]

46.4 (41.7, 51.2)

38.3 (31.9, 45.0)

OR (measurable disease) [% (95% CI)]

60.7 (55.2, 65.9)

49.1 (41.4, 56.9)

CBR [% (95% CI)]

85.8 (82.2, 88.9)

71.2 (64.7, 77.0)

N=number of patients; CI=confidence interval; NE=not estimable; OR=objective response; CBR=clinical

benefit response.

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

Figure 1. Kaplan-Meier plot of progression-free survival (Investigator assessment, intent-to-treat

population) – PALOMA-2 study

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

A series of prespecified subgroup PFS analyses was performed based on prognostic factors and baseline

characteristics to investigate the internal consistency of treatment effect. A reduction in the risk of disease

progression or death in favor of the palbociclib plus letrozole arm was observed in all individual patient

subgroups defined by stratification factors and baseline characteristics. This was evident for patients with

visceral metastases (HR of 0.67 [95% CI: 0.50, 0.89], median progression-free survival [mPFS] 19.2

months versus 12.9 months) or without visceral metastases (HR of 0.48 [95% CI: 0.34, 0.67], mPFS Not

Reached [NR] versus 16.8 months) and patients with bone only disease (HR of 0.36 [95% CI: 0.22, 0.59],

mPFS NR vs. 11.2 months) or without bone-only disease (HR of 0.65 [95% CI: 0.51, 0.84], mPFS 22.2

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 tumor tested positive for Rb protein

expression by immunohistochemistry (IHC) (HR of 0.531 [95% CI: 0.42, 0.68], mPFS 24.2 months

versus 13.7 months). The reduction in risk of disease progression or death in favor of the palbociclib plus

letrozole arm was not statistically significant in the 51 patients whose tumors tested negative for Rb

protein expression by IHC (HR of 0.675 [95% CI: 0.31, 1.48], mPFS NR versus 18.5 months).

Additional efficacy measures (OR and TTR) assessed in the sub-groups of patients with or without

visceral disease are displayed in Table 7.

Table 7. Efficacy results in visceral and non-visceral disease from PALOMA–2 study (intent-to-treat

population)

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)]

58.9(52.0, 65.5)

45.5

(35.9, 55.2)

34.8

(28.6, 41.3)

31.3

(22.8, 40.7)

TTR, Median [months (range)]

(2.0, 19.5)

(2.6, 16.6)

(2.1, 27.8)

(2.6, 22.3)

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 tumor response.

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, 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 (α=0.00135), demonstrating a statistically significant prolongation in PFS and a clinically

meaningful treatment effect.

A more mature update of efficacy data is reported in Table 8.

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)

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.

Figure 2. Kaplan-Meier plot of progression-free survival (investigator assessment, intent-to-treat

population) – PALOMA-3 study

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

A reduction in the risk of disease progression or death in the palbociclib plus fulvestrant arm was

observed in all individual patient subgroups defined by stratification factors and baseline characteristics.

This was evident for pre/perimenopausal women (HR of 0.46 [95% CI: 0.28, 0.75]) and postmenopausal

women (HR of 0.52 [95% CI: 0.40, 0.66]) and patients with visceral site of metastatic disease (HR of 0.50

[95% CI: 0.38, 0.65]) and non-visceral site of metastatic disease (HR of 0.48 [95% CI: 0.33, 0.71]).

Benefit was also observed regardless of lines of prior therapy in the metastatic setting, whether 0 (HR of

0.59 [95% CI: 0.37, 0.93]), 1 (HR of 0.46 [95% CI: 0.32, 0.64]), 2 (HR of 0.48 [95% CI: 0.30, 0.76]), or

≥3 lines (HR of 0.59 [95% CI: 0.28, 1.22]). Additional efficacy measures (OR and TTR) assessed in the

sub-groups of patients with or without visceral disease are displayed in Table 9.

Table 9. Efficacy results in visceral and non-visceral disease from PALOMA–3 study (Intent-to-

Treat population)

Visceral Disease

Non-visceral Disease

IBRANCE plus

fulvestrant

(N=206)

Placebo plus

fulvestrant

(N=105)

IBRANCE plus

fulvestrant

(N=141)

Placebo plus

fulvestrant

(N=69)

OR [%, (95% CI)]

35.0

(28.5, 41.9)

13.3

(7.5, 21.4)

13.5

(8.3, 20.2)

14.5

(7.2, 25.0)

TTR, Median [months (range)]

(3.5, 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

unconfirmed responses according to RECIST 1.1; TTR=time to first tumor response.

Patient-reported symptoms were assessed using the European Organization 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 C

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 C

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 AUC

and C

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 (f

) of palbociclib in human plasma in vivo increased incrementally with

worsening hepatic function. There was no obvious trend in the mean palbociclib f

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 [

C]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 [

C]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 AUC

) 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 C

) was increased by 7%, 38%

and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal

hepatic function. In addition, based on a population pharmacokinetic analysis that included 183 patients

with advanced cancer, where 40 patients had mild hepatic impairment based on National Cancer Institute

(NCI) classification (total bilirubin ≤ Upper Limit of Normal (ULN) and Aspartate Aminotransferase

(AST) > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect

on the pharmacokinetics of palbociclib.

Renal impairment

Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total

palbociclib exposure (AUC

) 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 (C

) 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 AUC

and C

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 C

. 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

Carcinogenicity studies have not been conducted with palbociclib.

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 nonclinical findings in rats and dogs. Palbociclib-related findings in the testis,

epididymis, prostate, and seminal vesicle included decreased organ weight, atrophy or degeneration,

hypospermia, intratubular cellular debris, lower sperm motility and density, and decreased secretion.

These findings were observed in rats and/or dogs at exposures ≥7 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

3 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 and other handling

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

requirements.

7. Marketing authorisation holder

Pfizer Limited

Ramsgate Road

Sandwich

Kent CT13 9NJ

United Kingdom

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

02/2018

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

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

Ref: IB 5_0

Company Contact Details

Pfizer Limited

Address

Ramsgate Road, Sandwich, Kent, CT13 9NJ

+44 (0)1304 656 221

Medical Information Website

www.pfizermedicalinformation.co.uk

Telephone

+44 (0)1304 616 161

Medical Information Direct Line

+44 (0)1304 616161

Similar products

Search alerts related to this product

View documents history

Share this information