Consumer medicine information

Ibrance

Palbociclib

BRAND INFORMATION

Brand name

Ibrance

Active ingredient

Palbociclib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ibrance.

What is in this leaflet

This leaflet answers some common questions about IBRANCE.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking IBRANCE against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What IBRANCE is used for

What IBRANCE does

IBRANCE is used to treat patients with hormone receptor-positive (HR-positive), human epidermal growth factor receptor 2 negative (HER2-negative) advanced breast cancer. It is given together with an aromatase inhibitor or fulvestrant, which are used as hormonal anticancer therapies.

IBRANCE belongs to a group of medicines called cyclin-dependent kinase inhibitors.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

IBRANCE is only available with a doctor's prescription.

It is not addictive.

Use in Children

The safety and efficacy of IBRANCE in children have not been established.

Before you take IBRANCE

When you must not take it

Do not take IBRANCE if you have an allergy to:

  • any medicine containing palbociclib
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have a fever, chills or any other signs or symptoms of infection.

Tell your doctor if you have or have had any of the following medical conditions:

  • abnormal blood test results
  • kidney problems
  • liver problems
  • lactose intolerance.

You should have a blood test before starting treatment with IBRANCE.

Tell your doctor if you are pregnant or plan to become pregnant. IBRANCE may affect the developing baby and should not be taken during pregnancy. It is recommended you use contraception whilst you take IBRANCE. Your doctor will discuss the risks with you.

IBRANCE may decrease fertility in men. Men may consider preserving sperm before taking IBRANCE.

Tell your doctor if you are breast-feeding. You should not breast feed if you are being treated with IBRANCE.

If you have not told your doctor about any of the above, tell him/her before you start taking IBRANCE.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including:

  • all prescription medicines
  • all medicines, vitamins, herbal supplements or natural therapies you buy without a prescription from a pharmacy, supermarket, naturopath or health food shop.

Some medicines may be affected by IBRANCE or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines. Your doctor will advise you.

Tell your doctor or pharmacist if you are taking any of the following:

  • medicines used to treat fungal infections such as posaconazole, voriconazole, ketoconazole, miconazole or itraconazole
  • antibiotics used to treat bacterial infections such as erythromycin or clarithromycin
  • medicines used to treat HIV infections/AIDS such as atazanavir, indinavir, efavirenz, ritonavir, lopinavir, fosamprenavir, nevirapine, etravirine or saquinavir
  • medicines used to treat hepatitis C such as elbasvir/grazoprevir
  • medicines used to treat tuberculosis (TB) such as rifampin or rifabutin,
  • medicines used to treat certain heart conditions or high blood pressure such as bosentan or diltiazem
  • medicines used to treat epilepsy, seizures or fits such as phenytoin, carbamazepine, felbamate, primidone or phenobarbital
  • St John's wort (Hypericum perforatum), a herbal medicine used to treat depression and other conditions
  • nefazodone, used to treat depression
  • modafinil, used to treat sleep disorders

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take IBRANCE

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you which strength of IBRANCE you need to take. This may depend on your age, your condition and whether or not you are taking any other medicines.

For advanced breast cancer the recommended dose of IBRANCE is one 125 mg capsule or tablet taken once daily for 21 days followed by 7 days without taking IBRANCE.

Your doctor may change your dose during treatment.

Taking IBRANCE for 21 continuous days followed by 7 days without taking IBRANCE (total of 28 days) is counted as one treatment cycle.

The 7 day break when you are not taking IBRANCE helps your body recover. It reduces your chance of getting side effects and could stop you getting an infection.

How to take it

Swallow the IBRANCE capsule or tablet whole with a glass of water. Do not chew, crush, open the capsules or split the tablets prior to swallowing.

When to take it

You should take IBRANCE capsules with food and at the same time each day. Taking it with food and at the same time each day will have the best effect. It will also help you remember when to take it.

You should take IBRANCE tablets at the same time each day and can take it with or without food.

How long to take it

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it or vomit after taking a dose

Take your next dose at your regular time.

Do not take a double dose to make up for the dose that you missed.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor, or Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much IBRANCE.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using IBRANCE

Things you must do

Make sure you follow your doctor's instructions and keep all appointments.

You should have a blood test before each treatment cycle. The blood test is done to make sure your blood cells have recovered from the last treatment cycle and to check for side effects.

Tell your doctor immediately if you experience signs or symptoms of an infection such as fever and chills. IBRANCE may reduce the number of your white blood cells and weaken your immune system. You may be at greater risk of getting an infection while you are taking IBRANCE.

Use contraception (birth control) to prevent pregnancy while you are being treated with IBRANCE. Women who could become pregnant or men who could father a child must use a reliable method of contraception during treatment with IBRANCE. Women should continue using contraception for at least a month after taking their last dose of IBRANCE and males should continue using contraception for 14 weeks after the last dose of IBRANCE.

Tell your doctor immediately if you become pregnant while taking IBRANCE.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking IBRANCE.

Things you must not do

Do not eat grapefruit or drink grapefruit juice while you are being treated with IBRANCE. Grapefruit and grapefruit juice may change the amount of IBRANCE in your body.

Do not take IBRANCE to treat any other complaints unless your doctor tells you to.

Do not give IBRANCE to anyone else, even if they have the same condition as you.

Do not stop taking IBRANCE or lower the dosage without checking with your doctor.

Things to be careful of

Be careful driving or operating machinery until you know how IBRANCE affects you. This medicine may cause fatigue and blurred vision in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Like all medicines, IBRANCE can cause side effects.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking IBRANCE.

Do not be alarmed by the list of side effects. You may not experience any of them.

Tell your doctor if...

Tell your doctor or pharmacist if you notice any of the following:

  • tiredness
  • nausea (feeling sick) or vomiting
  • diarrhoea
  • sore mouth, lips or tongue
  • hair loss
  • loss of appetite
  • nose bleed
  • skin rash
  • change in sense of taste
  • blurred vision, increased tearing or dry eyes

Go to hospital if...

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital, if you notice any of the following:

  • infection, fever, chills
  • mouth ulcers, sore throat, sore gums
  • lack of energy, pale skin, shortness of breath
  • weakness, dizziness, rapid heart rate
  • bleeding or bruising more easily than usual

The above side effects may be serious. You may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some people.

Some side effects can only be found when your doctor does tests to check your progress. These tests could show a reduction in white blood cells, red blood cells or platelets. These tests could also show a change in liver enzymes.

After using IBRANCE

Storage

Keep your IBRANCE in the original pack until it is time to take it. If you take the capsules or tablets out of the pack they may not keep well.

Keep your IBRANCE pack in a cool dry place where the temperature stays below 30°C.

Do not store IBRANCE or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

IBRANCE 75 mg:

Capsules: light orange cap and body printed with "Pfizer" on the cap and "PBC 75" on the body in white ink.

Tablets: round, light purple, film-coated tablet debossed with “Pfizer” on one side and “PBC 75” on the other side.

IBRANCE 100 mg:

Capsules: caramel cap and light orange body printed with "Pfizer" on the cap and "PBC 100" on the body in white ink.

Tablets: oval, green, film-coated tablet debossed with “Pfizer” on one side and “PBC 100” on the other side.

IBRANCE 125 mg:

Capsules: caramel cap and body printed with "Pfizer" on the cap and "PBC 125" on the body in white ink.

Tablets: oval, light purple, film-coated tablet debossed with “Pfizer” on one side and “PBC 125” on the other side.

Each capsule blister pack or bottle contains 21 capsules.

Each tablet blister pack contains 21 film-coated tablets.

Ingredients

IBRANCE capsules and tablets contain 75 mg, 100 mg or 125 mg of palbociclib as the active ingredient.

The capsules also contain:

  • microcrystalline cellulose
  • lactose monohydrate
  • sodium starch glycollate
  • silicon dioxide
  • magnesium stearate
  • gelatin
  • iron oxide red (E172)
  • iron oxide yellow (E172)
  • titanium dioxide (E171)

The tablets have a tablet core containing:

  • microcrystalline cellulose
  • silicon dioxide
  • crospovidone
  • magnesium stearate
  • succinic acid

The tablets also have a film coating containing:

  • hypromellose
  • titanium dioxide (E171)
  • triacetin
  • indigo carmine aluminium lake (E132)
  • iron oxide red (E172)
  • iron oxide yellow (E171)

IBRANCE does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

IBRANCE is supplied in Australia by:

Pfizer Australia Pty Ltd
Sydney, NSW
Toll Free number: 1800 675 229

Australian registration numbers

IBRANCE 75 mg:

AUST R 274622 (capsule blister)

AUST R 274624 (capsule bottle)

AUST R 319780 (tablet blister)

IBRANCE 100 mg:

AUST R 274623 (capsule blister)

AUST R 274621 (capsule bottle)

AUST R 319782 (tablet blister)

IBRANCE 125 mg:

AUST R 274619 (capsule blister)

AUST R 274620 (capsule bottle)

AUST R 319784 (tablet blister)

Date of preparation

This leaflet was prepared in June 2020.

® = Registered Trademark

© Pfizer Australia Pty Ltd

Published by MIMS August 2020

BRAND INFORMATION

Brand name

Ibrance

Active ingredient

Palbociclib

Schedule

S4

 

1 Name of Medicine

Palbociclib.

2 Qualitative and Quantitative Composition

Each Ibrance tablet contains palbociclib 75 mg, 100 mg or 125 mg.
Each Ibrance capsule contains palbociclib 75 mg, 100 mg or 125 mg.

Excipients with known effect.

Ibrance capsules contain lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ibrance is supplied as hard capsules or a film-coated tablets for oral administration.
75 mg strength: Opaque, hard capsule with a light orange body (printed "PBC 75" in white) and a light orange cap (printed "Pfizer" in white). Round, light purple, film-coated tablet debossed with "Pfizer" on one side and "PBC 75" on the other side.
100 mg strength: Opaque, hard capsule with a light orange body (printed "PBC 100" in white) and a caramel cap (printed "Pfizer" in white). Oval, green, film-coated tablet debossed with "Pfizer" on one side and "PBC 100" on the other side.
125 mg strength: Opaque, hard capsule with a caramel body (printed "PBC 125" in white) and a caramel cap (printed "Pfizer" in white). Oval, light purple, film-coated tablet debossed with "Pfizer" on one side and "PBC 125" on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Ibrance is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer in combination with:
an aromatase inhibitor as initial endocrine based therapy;
fulvestrant in patients who have received prior therapy.

4.2 Dose and Method of Administration

Dosage.

The recommended dose of Ibrance is a 125 mg capsule or tablet taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days.
When coadministered with palbociclib, an aromatase inhibitor should be administered according to the dose schedule reported in the Product Information for that aromatase inhibitor.
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 product information for fulvestrant.

Method of administration.

Ibrance capsules should be taken with food. Ibrance tablets may be taken with or without food.
Patients should be encouraged to take their dose at approximately the same time each day. Continue the treatment as long as the patient is deriving clinical benefit from therapy.
If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time. Ibrance capsules or tablets should be swallowed whole (do not chew, crush, open the capsules or split the tablets prior to swallowing). No capsule or tablet should be ingested if it is broken, cracked or otherwise not intact.
Prior to the start of, and throughout treatment, pre/perimenopausal women treated with the combination of Ibrance plus aromatase inhibitor/fulvestrant should also be treated with a luteinising hormone releasing hormone (LHRH) agonist according to local clinical practice. Pre- and perimenopausal women were not enrolled in PALOMA-1 and PALOMA-2.
For men treated with the combination of Ibrance plus aromatase inhibitor therapy, consider treatment with an LHRH agonist according to current clinical practice standards.

Dosage 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 Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).
Permanently discontinue Ibrance in patients with severe interstitial lung disease (ILD)/pneumonitis (see Section 4.4 Special Warnings and Precautions for Use, Interstitial lung disease (ILD)/pneumonitis).
No dose modifications are required on the basis of patient's age, sex or body weight (see Section 5.2 Pharmacokinetic Properties).

Dosage adjustment in renal impairment.

No dose adjustment 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 dosing recommendation in this patient population (see Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment).

Dosage adjustment in hepatic impairment.

No dose adjustment 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 for 21 consecutive days followed by 7 days off treatment (see Section 5.2 Pharmacokinetic Properties, Special Populations, Hepatic impairment).

Dosage adjustment in the elderly.

No dose adjustment is necessary in patients ≥ 65 years of age (see Section 5.2 Pharmacokinetic Properties, Special populations, Elderly ≥ 65 years).

Children and adolescents.

The safety and efficacy of Ibrance in children and adolescents < 18 years of age have not been established.

4.3 Contraindications

Use of Ibrance is contraindicated in patients with hypersensitivity to palbociclib or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

Myelosuppression.

Neutropenia.

Decreased neutrophil counts have been observed very commonly in clinical studies with Ibrance. In patients receiving Ibrance in combination with letrozole (PALOMA-1 and PALOMA-2) and in combination with fulvestrant (PALOMA-3), grade 3 (ANC 500-< 1000/mm3) and grade 4 (ANC < 500/mm3) decreased neutrophil counts were reported in 56.1% and 10.6% of patients respectively (see Section 4.8 Adverse Effects (Undesirable Effects)).
In PALOMA-1 and PALOMA-2 the median time to first episode of any grade neutropenia was 15 days (range 12-700 days) and 28 days (range 12-854) for grade ≥ 3 neutropenia. The median duration of grade ≥ 3 neutropenia was 33 days (range 1-534).
In PALOMA-3 the median time to first episode of neutropenia was 15 days (13-317 days) for any grade and 16 days (range 13-587) for grade ≥ 3 neutropenia. The median duration for grade ≥ 3 neutropenia was 21 days (range 1-167).
An increase in palbociclib exposure has been associated with more severe neutropenia; in Asian subjects, frequency of grade ≥ 3 neutropenia is higher than in white subjects (see Section 5.2 Pharmacokinetic Properties, Special populations, Asian race).
Febrile neutropenia has been reported in 1.6% of patients receiving palbociclib in combination with letrozole in PALOMA-2 and in 0.9% of patients receiving palbociclib in combination with fulvestrant in PALOMA-3. One death due to neutropenic sepsis was reported in PALOMA-3.
Febrile neutropenia has not been reported in PALOMA-1. Febrile neutropenia has been reported in about 2% of patients exposed to Ibrance across the overall clinical program (see Section 4.4 Special Warnings and Precautions for Use, Identified precautions, Infections).
Monitor full blood count 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.
Dosing 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 Section 4.2 Dose and Method of Administration).

Anaemia.

Anaemia has been observed very commonly in clinical studies with Ibrance. In patients receiving Ibrance in combination with letrozole (PALOMA-1 and PALOMA-2) and in combination with fulvestrant (PALOMA-3), grade 3 and grade 4 anaemia was observed in 4.8% and 0% of patients respectively (see Section 4.8 Adverse Effects (Undesirable Effects)).
In PALOMA-1 and PALOMA-2 the median time to first episode of any grade anaemia was 29 days (range 1-777 days) and 195 days (range 14-760) for grade ≥ 3 anaemia. The median duration of grade ≥ 3 anaemia was 7 days (range 1-125). In PALOMA-3 the median time to first episode of anaemia was 25 days (12-378 days) for any grade and 52 days (range 15-363) for grade ≥ 3 anaemia. The median duration for grade ≥ 3 anaemia was 7 days (range 1-125). Across both studies, supportive treatment with red blood cell growth factors and transfusions was administered in 2.4% and 1.7%, respectively, on the palbociclib arms, and in 0.4% and 0%, respectively on the comparator arms.

Thrombocytopenia.

Thrombocytopenia has been observed very commonly in clinical studies with Ibrance. In patients receiving Ibrance in combination with letrozole (PALOMA-1 and PALOMA-2) and in combination with fulvestrant (PALOMA-3), grade 3 and grade 4 thrombocytopenia was observed in 1.6% and 0.6% of patients, respectively (see Section 4.8 Adverse Effects (Undesirable Effects)).
In PALOMA-1 and PALOMA-2 the median time to first episode of any grade thrombocytopenia was 27 days (range 2-875 days) and 256 days (range 21-652 days) for grade ≥ 3 thrombocytopenia. The median duration of grade ≥ 3 thrombocytopenia was 7 days (range 1-28 days). In PALOMA-3 the median time to first episode of thrombocytopenia was 15 days (13-422 days) for any grade and 23 days (range 15-57) for grade ≥ 3 thrombocytopenia. The median duration for grade ≥ 3 thrombocytopenia was 7 days (range 1-9 days).

Interstitial lung disease (ILD)/pneumonitis.

Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin dependent kinase 4/6 (CDK4/6) inhibitors, including Ibrance when taken in combination with endocrine therapy.
Across clinical trials (PALOMA-1, PALOMA-2, PALOMA-3), 1.0% of Ibrance-treated patients had ILD/pneumonitis of any grade, 0.1% had Grade 3 or 4 and no fatal cases were reported (see Section 4.8). Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported.
Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis (e.g. hypoxia, cough, dyspneoa). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, interrupt Ibrance immediately and evaluate the patient. Permanently discontinue Ibrance in patients with severe ILD or pneumonitis (see Section 4.2).

Infections.

Since Ibrance has myelosuppressive properties, it may predispose to infections.
Infections of any grade have been reported at a higher rate in patients treated with Ibrance. Infections of any grade occurred in 59.6% of patients treated with Ibrance and letrozole in PALOMA-1 and PALOMA-2 compared to 40.1% of patients treated in the comparator arm. Infections of any grade occurred in 47.2% of patients treated with Ibrance and fulvestrant in PALOMA-3, compared to 31.4% of patients treated in the comparator arm.
Grade 3 and 4 infections occurred in 6.5% of patients treated with Ibrance and letrozole in PALOMA-1 and PALOMA-2 compared to 2.3% of patients treated in the comparator arm. Grade 3 and 4 infections occurred in 3.2% of patients treated with Ibrance in PALOMA-3 compared to 2.9% of patients treated in the comparator arm.
Monitor patients for signs and symptoms of infection and treat as medically appropriate (see Section 4.8 Adverse Effects (Undesirable Effects)).
Physicians should inform patients to immediately report any episodes of fever.

Use in hepatic impairment.

See Section 4.2 Dose and Method of Administration, Dosage adjustment in hepatic impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Hepatic impairment.

Use in renal impairment.

See Section 4.2 Dose and Method of Administration, Dosage adjustment in renal impairment; Section 5.2 Pharmacokinetic Properties, Special populations, Renal impairment.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Dosage adjustment in the elderly; Section 5.2 Pharmacokinetic Properties, Special populations, Elderly (≥ 65 years).

Paediatric use.

The safety and efficacy of Ibrance in paediatric patients have not been studied.

Effects on laboratory tests.

See Section 4.4 Special Warnings and Precautions for Use, Identified precautions, Myelosuppression.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Palbociclib is primarily metabolised by CYP3A and sulfotransferase (SULT) enzyme SULT2A1. In vivo, palbociclib is a time dependent inhibitor of CYP3A.

Agents that may increase palbociclib plasma concentrations.

Effect of CYP3A inhibitors.

Data from a drug drug interaction (DDI) study in healthy subjects indicate that coadministration of multiple 200 mg doses of itraconazole with a single 125 mg dose of Ibrance increased palbociclib total exposure (area under the curve, AUCinf) and the maximum observed plasma concentration (Cmax) by approximately 87% and 34%, respectively, relative to a single 125 mg dose of Ibrance given alone. The concomitant use of strong CYP3A inhibitors including, but not limited to, amprenavir, atazanavir, boceprevir, clarithromycin, conivaptan, delavirdine, diltiazem, erythromycin, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole and grapefruit or grapefruit juice should be avoided.

Agents that may decrease palbociclib plasma concentrations.

Effect of CYP3A inducers.

Data from a DDI study in healthy subjects indicate that coadministration of multiple 600 mg doses of rifampin, a strong CYP3A inducer, with a single 125 mg dose of Ibrance decreased palbociclib AUCinf and Cmax by 85% and 70%, respectively, relative to a single 125 mg dose of Ibrance given alone. Data from a DDI study in healthy subjects indicate that coadministration of multiple 400 mg daily doses of modafinil, a moderate CYP3A inducer, with a single 125 mg Ibrance dose decreased palbociclib AUCinf and Cmax by 32% and 11%, respectively, relative to a single 125 mg dose of given alone.
The concomitant use of strong CYP3A inducers including, but not limited to, carbamazepine, enzalutamide, felbamate, nevirapine, phenobarbital, phenytoin, primidone, rifabutin, rifampin, rifapentin and St. John's wort should be avoided.
Coadministration of a moderate CYP3A inducer (modafinil) decreased the plasma exposure of palbociclib in healthy subjects by 32%. Moderate CYP3A inducers (e.g. bosentan, efavirenz, etravirine, modafinil and nafcillin) can be used concurrently with Ibrance when unavoidable. No dosing adjustments are required.

Effect of acid reducing agents.

Ibrance capsules.

Data from a DDI study in healthy subjects indicated that coadministration of a single 125 mg dose of Ibrance capsules with multiple doses of the proton pump inhibitor (PPI) rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease) compared with a single 125 mg Ibrance capsule administered alone.
Given the reduced effect on gastric pH of H2-receptor antagonists and local antacids compared to PPIs under fed conditions, there is no clinically relevant effect of PPIs, H2-receptor antagonists or local antacids on palbociclib exposure.
Data from another DDI study in healthy subjects indicated that coadministration of a single Ibrance capsule with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared with a single 125 mg Ibrance capsule administered alone.
Therefore, Ibrance capsules should be taken with food (see Section 4.2 Dose and Method of Administration).

Ibrance film-coated tablets.

Coadministration of multiple doses of the PPI rabeprazole with a single 125 mg Ibrance tablet under fasted conditions had no effect on the rate and extent of absorption of palbociclib when compared to a single 125 mg Ibrance tablet administered alone (see Section 4.2 Dose and Method of Administration).

Effects of Ibrance on other drugs.

Palbociclib is a weak time-dependent inhibitor of CYP3A following daily 125 mg dosing at steady state in humans. In a DDI study in healthy subjects, coadministration of midazolam with multiple doses of palbociclib increased the midazolam AUCinf and Cmax values by 61% and 37%, respectively, as compared with administration of midazolam alone.
In vitro, palbociclib is not an inhibitor of CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19 or 2D6 and is not an inducer of CYP1A2, 2B6, 2C8 or 3A4 at clinically relevant concentrations.

Letrozole.

Data from a clinical study in patients with breast cancer showed that there was no drug interaction between palbociclib and letrozole when the 2 drugs were coadministered.

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 2 drugs were coadministered.

Goserelin.

Data from a clinical study in patients with breast cancer showed that there was no clinically relevant drug interaction between palbociclib and goserelin when the 2 drugs were coadministered.

In vitro studies with transporters.

In vitro evaluations indicate that palbociclib has a low potential to inhibit the activities of drug transporters P-glycoprotein (P-gp, systemically), breast cancer resistance protein (BCRP, systemically), 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. Based on in vitro data, palbociclib has the potential to inhibit OCT1 at clinically relevant concentrations, as well as the potential to inhibit P-gp or BCRP in the gastrointestinal tract at the proposed clinical dose. Based on in vitro data, palbociclib was a weak substrate for P-gp and a moderate substrate for BCRP; however, P-gp and BCRP mediated transport are unlikely to significantly affect the extent of oral absorption of palbociclib at therapeutic doses.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Palbociclib did not affect oestrous cycling, 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). However, no clinical data have been obtained on fertility in human females. Based on nonclinical safety findings, male fertility may be compromised by treatment with Ibrance. Men should consider sperm preservation prior to beginning therapy with Ibrance.
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 ≥ 6 times or subtherapeutic compared to human clinical exposure based on AUC, respectively. The effects appeared to be reversible.
(Category D)
There are no adequate and well controlled studies in pregnant women receiving Ibrance. Based on findings in animals and mechanism of action, palbociclib can cause fetal harm when administered to a pregnant woman.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving Ibrance. Women of childbearing potential who are receiving this drug should use adequate contraceptive methods during therapy and for at least a month after completing therapy. Partners of females of childbearing potential receiving this drug should use adequate contraception methods during therapy and for at least 14 weeks after completing therapy.
Palbociclib was fetotoxic in pregnant rats and rabbits. Reduced fetal 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 (6 times human clinical exposure based on AUC). An increased incidence of a skeletal variation (increased incidence of a rib present at the seventh cervical vertebra) at ≥ 100 mg/kg/day (equivalent to human clinical exposure based on AUC) was seen in rats while other skeletal variations and skeletal ossification were seen in rabbits at ≥ 10 mg/kg/day (3 times human clinical exposure based on AUC). Actual fetal exposure and cross placenta transfer have not been examined.
CDK4/6 double knockout mice have been reported to die in late stages of fetal development due to severe anaemia. However, knockout mouse data may not be predictive of effects in humans due to differences in degree of target inhibition.
Female patients taking palbociclib during pregnancy or who become pregnant while taking palbociclib should be apprised of the potential hazard to the fetus.
No studies have been conducted in humans to assess the effect of Ibrance on milk production, its presence in breast milk or its effects on the breastfed child. It is unknown whether palbociclib is excreted in human milk. Patients receiving Ibrance should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Ibrance on the ability to drive or operate machinery have been conducted. However, patients experiencing fatigue while taking Ibrance should exercise caution when driving or operating machinery.

4.8 Adverse Effects (Undesirable Effects)

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.

PALOMA-1 and PALOMA-2: patients treated with the combination Ibrance plus letrozole.

The safety profile of Ibrance (125 mg/day) in combination with letrozole (2.5 mg/day) versus the comparator arm is based on data from PALOMA-1 and PALOMA-2. Table 4 shows the adverse reactions observed in 527 patients with HR-positive, HER2-negative advanced breast cancer who received at least 1 dose of Ibrance plus letrozole in PALOMA-1 and PALOMA-2. See Table 5.
The most common adverse reactions (≥ 20%) of any grade reported in patients in the Ibrance plus letrozole arm by descending frequency were neutropenia, infections, leukopenia, nausea, fatigue, alopecia, stomatitis, anaemia and diarrhoea.
Dose reductions due to an adverse event of any grade occurred in 36.2% of patients receiving Ibrance plus letrozole in PALOMA-1 and PALOMA-2. No dose reductions were allowed for the comparator arm. Permanent treatment discontinuation associated with an adverse event occurred in 10.6% patients receiving Ibrance plus letrozole in PALOMA-1 and PALOMA-2 and in 5.0% of patients in the comparator arm.
In PALOMA-2 patients receiving Ibrance plus letrozole, the starting dose of Ibrance was 125 mg once daily. Dose reductions to 100 mg occurred in 36% of patients and dose reductions to 75 mg occurred in 14% of patients due to adverse events.
Neutropenia of any grade was reported in 78.9% of patients receiving Ibrance plus letrozole in PALOMA 1 and PALOMA-2, with grade 3 neutropenia reported in 55.2% of patients and grade 4 neutropenia reported in 9.7% of patients (see Section 4.4 Special Warnings and Precautions for Use).
The most frequently reported grade > 3 adverse reactions (≥ 5%) in patients receiving Ibrance plus letrozole by descending frequency were neutropenia, leukopenia, infections and anaemia.
The most frequently (≥ 1%) reported serious adverse drug reactions in patients receiving palbociclib plus letrozole (PALOMA-1 and PALOMA-2) were infections (4.6%) and febrile neutropenia (1.3%).
Cataract was reported in 3.2% of patients receiving Ibrance plus letrozole and in 0.5% of patients receiving placebo plus letrozole in PALOMA-2.

PALOMA-3: patients treated with the combination Ibrance plus fulvestrant.

The safety of Ibrance (125 mg/day) plus fulvestrant (500 mg) versus placebo plus fulvestrant was evaluated in PALOMA-3. Table 6 shows the adverse reaction in patients with HR-positive, HER2-negative advanced or metastatic breast cancer who received at least 1 dose of Ibrance plus fulvestrant. See Table 7.
The most common adverse drug reactions of any grade reported in > 20% of patients receiving palbociclib in combination with fulvestrant were neutropenia, leukopenia, infections, fatigue, nausea, anaemia, stomatitis, diarrhoea and thrombocytopenia.
Dose reductions due to an adverse event of any grade occurred in 35.9% of patients receiving Ibrance plus fulvestrant. No dose reduction was allowed for fulvestrant in PALOMA-3. Permanent treatment discontinuation associated with an adverse event occurred in 5.5% of patients receiving Ibrance plus fulvestrant and in 3.5% of patients receiving placebo plus fulvestrant.
In PALOMA-3 patients receiving Ibrance plus fulvestrant, the starting dose of Ibrance was 125 mg once daily. Dose reductions to 100 mg occurred in 34% of patients and dose reductions to 75 mg occurred in 12% of patients due to adverse events.
Neutropenia of any grade was reported in 83.2% of patients receiving Ibrance in combination with fulvestrant in PALOMA-3, with grade 3 neutropenia being reported in 55.4% of patients and grade 4 neutropenia being reported in 10.7% of patients (see Section 4.4 Special Warnings and Precautions for Use).
The most frequently (≥ 1%) reported serious adverse drug reactions in patients receiving palbociclib plus fulvestrant (PALOMA-3) were infections (4.1%), pyrexia (1.4%) and neutropenia (1.2%).

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is no known antidote for palbociclib. The treatment of Ibrance overdose should consist of general supportive measures. For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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 efficacy against luminal breast cancers, particularly oestrogen receptor (ER)-positive breast cancers. Mechanistic analyses revealed that the combination of palbociclib with anti-oestrogen agents enhanced the re-activation of retinoblastoma (Rb) through inhibition of Rb phosphorylation resulting in reduced E2F signalling and growth arrest.
The enhanced growth arrest of the ER-positive breast cancer cell lines treated with palbociclib and anti-oestrogen agents is accompanied by increased cell senescence resulting in a sustained cell cycle arrest following drug removal and increased cell size associated with a senescent phenotype. 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. This supports the contribution of senescence associated growth arrest as a mechanism associated with the antitumour efficacy of combined palbociclib/ER antagonist in ER-positive breast cancer models.
In the presence or absence of an anti-oestrogen, palbociclib treated bone marrow cells did not become senescent and resumed proliferation following palbociclib withdrawal, consistent with pharmacologic quiescence. The in vitro breast cancer cells, conversely, became senescent following palbociclib or anti-oestrogen treatment with additive effects in combination and remained arrested in the presence of anti-oestrogen.

Mechanism of action.

Palbociclib is a small molecule 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.

Clinical trials.

Study A5481003: randomised phase 1/2 study of Ibrance in combination with letrozole (PALOMA-1).

The efficacy of palbociclib was evaluated in a randomised, open label, multicentre study of palbociclib plus letrozole versus letrozole alone conducted in postmenopausal women with ER-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer who did not receive previous systemic treatment for their advanced disease.
The study was comprised of a limited phase 1 portion (N = 12), designed to confirm the safety and tolerability of the combination palbociclib plus letrozole, followed by a randomised phase 2 portion (N = 165), designed to evaluate the efficacy and safety of palbociclib in combination with letrozole compared with letrozole alone in the first line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. Randomisation was stratified by disease site (visceral versus bone only versus other) and by disease free interval (> 12 months from the end of adjuvant treatment to disease recurrence versus ≤ 12 months from the end of adjuvant treatment to disease recurrence or de novo advanced disease).
The patient demographic and baseline characteristics were generally balanced between the study arms in terms of age, race, disease sites, stage and prior therapies.
The primary endpoint of the study was investigator assessed progression free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. The median PFS (mPFS) for patients in the palbociclib plus letrozole arm was 20.2 months (95% confidence interval [CI]: 13.8-27.5) and 10.2 months (95% CI: 5.7-12.6) for patients in the letrozole alone arm. The observed hazard ratio (HR) was 0.488 (95% CI: 0.319-0.748) in favour of palbociclib plus letrozole, with a stratified log rank test 1-sided p-value of 0.0004.
At the final overall survival (OS) analysis, the observed HR was 0.897 (95% CI: 0.623, 1.294) with a stratified 1-sided p-value of 0.2812. The median OS in the palbociclib plus letrozole arm was 37.5 months (95% CI: 31.4, 47.8) and in the letrozole alone arm was 34.5 months (95% CI: 27.4, 42.6).
The estimated survival probabilities at 12, 24, and 36 months between the 2 treatment arms were 89.0% versus 87.0%, 77.9% versus 71.1%, and 50.8% versus 47.4%, in favor of palbociclib plus letrozole, respectively.

Study A5481008: randomised, phase 3 study of Ibrance in combination with letrozole (PALOMA-2).

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 or metastatic breast cancer who had not received prior systemic treatment for their advanced disease, whose disease was not amenable to resection or radiation therapy with curative intent, and for whom chemotherapy was not clinically indicated based on investigator's best medical judgement.
A total of 666 postmenopausal women were randomised 2:1 to either the palbociclib plus letrozole arm or to the placebo plus letrozole arm and were stratified by site of disease (visceral, non-visceral), disease free interval from the end of (neo)adjuvant treatment to disease recurrence (de novo metastatic, ≤ 12 months from the end of adjuvant treatment to disease recurrence, > 12 months from the end of adjuvant treatment to disease recurrence) and by the type of prior (neo)adjuvant anticancer therapies (prior hormonal therapy, no prior hormonal therapy).
Patients continued to receive their 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 disease 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). A detailed summary of the demographics and baseline characteristics are presented in Table 8.
The primary endpoint of the study was PFS evaluated according to RECIST version 1.1 as assessed by investigator. Secondary efficacy endpoints included objective response (OR), duration of response (DOR), clinical benefit response (CBR), overall survival (OS), safety, EQ-5D scores and health related quality of life (QoL) assessed using the Functional Assessment of Cancer Therapy Breast (FACT-B) questionnaire.
At the data cutoff date of 26-February-2016, the study met its primary objective of improving PFS. The HR was 0.576 (95% CI: 0.463, 0.718) in favour of palbociclib plus letrozole, with a stratified log rank test 1-sided p-value of < 0.000001. An updated analysis of the primary and secondary endpoints was performed after an additional 15 months of follow up (data cutoff date: 31-May-2017). A total of 405 PFS events were observed; 245 events (55.2%) in the palbociclib plus letrozole arm and 160 (72.1%) in the comparator arm.
Table 9 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.
The Kaplan-Meier curves for PFS based on the updated cutoff date of 31 May 2017 are displayed in Figure 1.
Prespecified subgroup analyses indicated that the treatment effect (by median PFS) was consistent in all subgroups defined by stratification factors and baseline characteristics, including presence/absence of visceral metastases at baseline and presence of bone-only disease at baseline. An exploratory analysis showed that median PFS was longer in the palbociclib plus letrozole arm for 512 patients whose tumour tested positive for Rb protein expression by immunohistochemistry (IHC) (HR 0.543 [95% CI: 0.433, 0.681], mPFS 27.4 months versus 13.7 months). For the 51 patients whose tumours tested negative for Rb protein expression by IHC, the difference between treatment arms was not statistically significant.
Patients with advanced, symptomatic visceral spread at risk of life threatening complications in the short term were not included in PALOMA-2.
At the time of the updated analyses for PFS, time to initiation of subsequent anticancer therapies was also assessed. The results from these analyses are shown in Table 10.
The overall survival (OS) data were not mature at the time of the final PFS analysis (20% of patients had died). Patients will continue to be followed for the final analysis.
An analysis of time to deterioration composite endpoint (TTD) in Functional Assessment of Cancer Therapy Breast (FACT-B), defined as the time between baseline and first occurrence of decrease of ≥ 7 points in FACT-B scores, was carried out based on survival analysis methods using a Cox proportional hazards model and log rank test. No statistically significant difference was observed in TTD in FACT-B total scores between the palbociclib plus letrozole arm and the placebo plus letrozole arm (HR of 1.042 [95% CI: 0.838, 1.295]; 1-sided p-value = 0.663.
Pre- and perimenopausal women were not enrolled in PALOMA-1 or PALOMA-2.

Study A5481023: randomised, phase 3 study of Ibrance in combination with fulvestrant (PALOMA-3).

The efficacy of palbociclib in combination with fulvestrant versus placebo plus fulvestrant was evaluated in an international, randomised, double blind, parallel group, multicentre study conducted in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer, regardless of their menopausal status, whose disease progressed after prior endocrine therapy and was not amenable to resection or radiation therapy with curative intent based on investigator's best medical judgement.
A total of 521 pre/postmenopausal women whose disease had progressed on or within 12 months after completion of adjuvant endocrine therapy or on or within 1 month from prior endocrine therapy for advanced disease were randomised 2:1 to the palbociclib plus fulvestrant arm or the placebo plus fulvestrant arm and stratified by documented sensitivity to prior hormonal therapy, menopausal status at study entry (pre/peri versus postmenopausal) and presence of visceral metastases. Crossover between treatment arms was not allowed.
Patients were balanced 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). The majority of patients in each treatment arm were white, had documented sensitivity to prior hormonal therapy and were postmenopausal. All patients had received prior systemic therapy and most patients in each treatment arm had received a previous chemotherapy regimen. More than half (62%) had an ECOG performance status of 0, 60% had visceral metastases and 60% had received more than 1 prior hormonal regimen for their primary diagnosis. See Table 11.
The primary endpoint of the study was investigator assessed PFS evaluated according to RECIST version 1.1. Secondary PFS analyses were based on a random sample Blinded Independent Central Radiology Review (BICR) of 40.5% of the ITT population. Secondary endpoints included OR, DOR, CBR, OS, safety, change in QoL and TTD. Patient reported outcomes including Global QoL and pain were measured using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30) and the Breast Cancer Module (BR23) questionnaire.
The study met its primary endpoint of prolonging investigator assessed PFS at the interim analysis conducted on 82% of the planned PFS events at final analysis; 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. The estimated HR from the stratified analysis was 0.422 (95% CI: 0.318, 0.560; 1-sided p < 0.000001) in favour of palbociclib plus fulvestrant. The mPFS was 9.2 months (95% CI: 7.5-not estimable [NE]) in the palbociclib plus fulvestrant arm and 3.8 months (95% CI: 3.5-5.5) in the placebo plus fulvestrant arm.
A more mature update of efficacy data is reported in Figure 2 and Table 12.
Prolongation of PFS in the palbociclib plus fulvestrant arm was also demonstrated in most individual patient subgroups supporting internal consistency of PFS benefit findings within the study and was supported by the secondary PFS random sample BICR audit. See Figure 3.
As per inclusion criteria, pre/perimenopausal women were enrolled in the study if already treated with an LHRH agonist from at least 4 weeks. If they were not treated with goserelin prior to study entry, they were switched to goserelin when they started the study treatment.
In the palbociclib plus fulvestrant arm 70 pre/perimenopausal women received goserelin for the duration of the study and in the placebo plus fulvestrant arm 36 pre/perimenopausal women received goserelin.
The palbociclib plus fulvestrant arm demonstrated similar clinical benefit in the pre/perimenopausal patient population (HR = 0.494 [95% CI: 0.300, 0.813]) and postmenopausal population (HR = 0.508 [95% CI: 0.395, 0.652]). Similarly, the mPFS for the palbociclib plus fulvestrant arm was 11.3 months (95% CI: 7.5, 15.0) in the pre/perimenopausal setting versus 11.2 months (95% CI: 9.5, 12.7) in the postmenopausal setting; while the mPFS in the placebo plus fulvestrant arm was 5.6 months (95% CI: 1.7, 9.2) in the pre/perimenopausal setting versus 3.9 months (95% CI: 3.5, 5.5) in the postmenopausal setting.
The overall survival (OS) data were not mature at the time of the final PFS analysis (11% of patients had died). Patients will continue to be followed for the final analysis.
Patient reported symptoms were assessed using the EORTC QLQ-C30 and EORTC QLQ-BR23. A total of 335 patients in the palbociclib plus fulvestrant arm and 166 patients in the placebo plus fulvestrant arm completed the questionnaire at baseline and at least 1 postbaseline visit.
Time to Deterioration (TTD) was prespecified as time between baseline and first occurrence of ≥ 10-point increase from baseline in pain symptom scores. Addition of palbociclib to fulvestrant resulted in a symptom benefit by significantly delaying TTD in pain symptom scores 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).
After a median follow-up time of 45 months, the final OS analysis was performed based on 310 events (59.5% of randomised patients). A clinically meaningful 6.9-month improvement in median OS in the palbociclib plus fulvestrant arm compared with the placebo plus fulvestrant arm was observed, although this result was not statistically significant at the prespecified significance level of 0.0235. A higher proportion of patients in the placebo plus fulvestrant arm received post-progression systemic treatments overall in comparison with the patients in the palbociclib plus fulvestrant arm (80.5% versus 71.8%) respectively. Also, in placebo plus fulvestrant arm, 15.5% of randomised patients received palbociclib and other CDK inhibitors as post progression subsequent treatments.
The results from the final OS data from PALOMA-3 Study are presented in Table 13. The relevant Kaplan-Meier plots are shown in Figures 2 and 4.
A positive treatment effect of palbociclib plus fulvestrant versus placebo plus fulvestrant on OS was observed in the majority of the prespecified subgroups. Due to the low event number and smaller sample size in some of the prespecified subgroups, the magnitude of estimated effect of palbociclib added to fulvestrant could not always be determined. The OS results from patients subgroups defined by stratification factors at randomisation are reported in Table 14.
The estimated survival probabilities for palbociclib plus fulvestrant versus placebo plus fulvestrant were respectively: 65.3% (95% CI: 59.9, 70.2) vs. 57.3% (95% CI: 49.2, 64.6) at 2 years and 49.6% (95% CI: 44.0, 54.9) vs. 40.8% (95% CI: 32.9, 48.5) at 3 years.
Men were not enrolled in PALOMA-1, PALOMA-2 and PALOMA-3.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of palbociclib were characterised in patients with solid tumours including advanced breast cancer and in healthy volunteers.

Absorption.

The time to Cmax (Tmax) of palbociclib is generally between 6 to 12 hours following oral administration of Ibrance capsules. The Tmax of palbociclib is generally observed between 4 to 12 hours following oral administration of Ibrance tablets. The mean absolute bioavailability of palbociclib after an oral 125 mg dose is 46%. In the dosing range of 25 mg to 225 mg, the AUC and Cmax increase proportionally with dose in general. Steady state was achieved within 8 days following repeated once daily dosing. With repeated once daily administration, palbociclib accumulates with a median accumulation ratio of 2.4 (range 1.5-4.2).

Food effect.

Ibrance capsules.

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. Therefore, food intake reduced the intersubject variability of palbociclib exposure, which supports administration of Ibrance capsules with food.
Compared to palbociclib given under overnight fasted conditions, the AUCinf and Cmax of palbociclib increased by 21% and 38% when given with high fat food, by 12% and 27% when given with low fat food and by 13% and 24% when moderate fat food was given 1 hour before and 2 hours after palbociclib dosing. In addition, food intake significantly reduced the intersubject and intrasubject variability of palbociclib exposure. Based on these results, Ibrance capsules should be taken with food.

Ibrance film-coated tablets.

The AUCinf and Cmax of palbociclib increased by 22% and 26%, respectively, when Ibrance tablets were given with a high-fat, high-calorie meal (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), and by 9% and 10%, respectively, when Ibrance tablets were given with a moderate fat, standard-calorie meal (approximately 500 to 700 calories with 75 to 105, 250 to 350, and 175 to 245 calories from protein, carbohydrate, and fat, respectively), compared to Ibrance tablets given under overnight fasted conditions. Based on these results, Ibrance tablets may be taken with or without food.

Gastric pH elevating medication effect.

Ibrance capsules.

In a healthy subject study, coadministration of a single 125 mg Ibrance capsule with multiple doses of the PPI rabeprazole under fed conditions decreased palbociclib Cmax by 41%, but had limited impact on AUCinf (13% decrease), when compared to a single 125 mg Ibrance capsule administered alone. Given the reduced effect on gastric pH of H2 receptor antagonists and local antacids compared to PPIs, the effect of these classes of acid-reducing agents on palbociclib exposure under fed conditions is expected to be minimal. Under fed conditions there is no clinically relevant effect of PPIs, H2-receptor antagonists or local antacids on palbociclib exposure. In another healthy subject study, coadministration of a single 125 mg Ibrance capsule with multiple doses of the PPI rabeprazole under fasted conditions decreased palbociclib AUCinf and Cmax by 62% and 80%, respectively, when compared with a single 125 mg Ibrance capsule administered alone.

Ibrance film-coated tablets.

Coadministration of multiple doses of the PPI rabeprazole with a single 125 mg Ibrance tablet under fasted conditions had no effect on the rate and extent of absorption of palbociclib when compared to a single 125 mg Ibrance tablet administered alone.

Distribution.

Binding of palbociclib to human plasma proteins in vitro was ~85%, with no concentration dependence over the concentration range of 500 nanogram/mL to 5000 nanogram/mL. The mean fraction unbound (fu) of palbociclib in human plasma in vivo increased incrementally with worsening hepatic function. There was no obvious trend in the mean palbociclib fu in human plasma in vivo with worsening renal function. The geometric mean apparent volume of distribution (Vz/F) was 2583 (26%) L.

Metabolism.

In vitro and in vivo studies indicate that palbociclib undergoes extensive hepatic metabolism in humans. Following oral administration of a single 125 mg dose of [14C] palbociclib to humans, the major primary metabolic pathways for palbociclib involved oxidation and sulfonation, with acylation and glucuronidation contributing as minor pathways. Palbociclib was the major circulating drug derived entity in plasma. The major circulating metabolite was a glucuronide conjugate of palbociclib, although it only represented 1.5% of the administered dose in the excreta. The glucuronide metabolite is primarily formed by UGT1A1 and to a lesser extent, by UGT1A4. 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 sulfotransferase (SULT) enzymes indicated that CYP3A and SULT2A1 are mainly involved in the metabolism of palbociclib.

Excretion.

The geometric mean apparent oral clearance (CL/F) of palbociclib was 63.08 L/h and the mean plasma elimination half-life was 28.8 hours in patients with advanced breast cancer. In 6 healthy male subjects given a single oral dose of [14C] palbociclib, a median of 91.6% of the total administered radioactive dose was recovered in 15 days; faeces (74.1% of dose) was the major route of excretion, with 17.5% of the dose recovered in urine. Excretion of unchanged palbociclib in faeces and urine was 2.3% and 6.9% of the administered dose, respectively.

Special populations.

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 37.9 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.

Elderly (≥ 65 years).

Of 444 patients who received palbociclib in study A5481008 (PALOMA-2), 181 patients (41%) were ≥ 65 years of age with 133 (30%) patients between the age of 65 and 74, and 48 (11%) patients ≥ 75 years of age. Of 347 patients who received palbociclib in study A5481023 (PALOMA-3), 86 patients (25%) were ≥ 65 years of age with 59 (17%) patients between the age of 65 and 74, and 27 (8%) patients ≥ 75 years of age. No overall differences in safety were observed across all age groups and elderly age groups. Neutropenia was the most common adverse event with palbociclib across all age groups; however, the incidence of febrile neutropenia was low in all age groups. No overall differences effectiveness of palbociclib were observed between these patients and younger patients.

Children and adolescents.

Pharmacokinetics of palbociclib have not been evaluated in patients ≤ 18 years of age.

Renal impairment.

Data from a pharmacokinetic trial in subjects with varying degrees of renal function indicate that total palbociclib exposure (AUCinf) was increased by 39%, 42%, and 31% with mild (60 mL/min ≤ CrCl < 90 mL/min), moderate (30 mL/min ≤ CrCl < 60 mL/min), and severe (CrCl < 30 mL/min) renal impairment, respectively, relative to subjects with normal (CrCl ≥ 90 mL/min) renal function. Peak palbociclib exposure (Cmax) was increased by 17%, 12%, and 15% for mild, moderate, and severe renal impairment, respectively, relative to subjects with normal renal function. This study included a small number of patients with severe renal impairment (n=6) and palbociclib use in this population is considered largely uncharacterised.
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 PK of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients requiring haemodialysis.

Hepatic impairment.

Data from a pharmacokinetic trial in subjects with varying degrees of hepatic function indicate that palbociclib unbound exposure (unbound AUCinf) decreased by 17% in subjects with mild hepatic impairment (Child-Pugh class A), and increased by 34% and 77% in subjects with moderate (Child-Pugh class B) and severe hepatic impairment (Child-Pugh class C), respectively, relative to subjects with normal hepatic function. This study included a small number of patients with severe hepatic impairment (n=7) and palbociclib use in this population is considered largely uncharacterised.
Peak palbociclib unbound exposure (unbound Cmax) was increased by 7%, 38% and 72% for mild, moderate and severe hepatic impairment, respectively, relative to subjects with normal hepatic function. In addition, based on a population pharmacokinetic analysis that included 183 patients with advanced cancer where 40 patients had mild hepatic impairment based on National Cancer Institute (NCI) classification (total bilirubin ≤ Upper Limit of Normal (ULN) and Aspartate Aminotransferase (AST) > ULN, or total bilirubin > 1.0 to 1.5 x ULN and any AST), mild hepatic impairment had no effect on the PK of palbociclib.

Asian race.

In a dedicated PK study in healthy volunteers, palbociclib geometric mean AUCinf and Cmax values were 30% and 35% higher, respectively, in Japanese subjects compared with non-Asian subjects after a single oral dose. However, this finding was not reproduced consistently in subsequent studies in breast cancer patients after multiple dosing. Based on an analysis of the cumulative pharmacokinetic, safety and efficacy data, no dose adjustment based on Asian race is considered necessary.

Cardiac electrophysiology.

The effect of palbociclib on the QT interval corrected for heart rate (QTc) was evaluated using time-matched electrocardiograms (ECGs) evaluating the change from baseline and corresponding pharmacokinetic data in 77 patients with breast cancer. Palbociclib did not prolong QTc to any clinically relevant extent at the recommended dose of 125 mg daily for 21 consecutive days followed by 7 days off treatment.

5.3 Preclinical Safety Data

The primary target organ findings following single and/or repeat dosing included haematolymphopoietic and male reproductive organ effects in rats and dogs, and effects on bone and actively growing incisors in rats only. These systemic toxicities were generally observed at clinically relevant exposures based on AUC. Partial to full reversal of effects on the haematolymphopoietic, male reproductive systems and incisor teeth were established, whereas the bone effect was not reversed following a 12 week nondosing period. The effect on bone indicate a potential risk for children and adolescents. In addition, cardiovascular effects (QTc prolongation, decreased heart rate and increased RR interval and systolic blood pressure) were identified in telemetered dogs at ≥ 4 times human clinical exposure based on Cmax.

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 rats.

Carcinogenicity.

Palbociclib was assessed for carcinogenicity in a 6-month transgenic mouse study and in a 2-year rat study. Palbociclib was negative for carcinogenicity in transgenic mice at doses up to 60 mg/kg/day (No Observed Effect Level [NOEL] approximately 7 times human clinical exposure based on AUC). Palbociclib was carcinogenic in rats. Palbociclib-related neoplastic finding in rats included an increased incidence of microglial cell tumors in the central nervous system of males at 30 mg/kg/day (5 times human clinical exposure based on AUC). There were no neoplastic findings in female rats at any dose up to 200 mg/kg/day. The NOEL for palbociclib-related carcinogenicity effects was 10 mg/kg/day (approximately 2 times the human clinical exposure based on AUC) and 200 mg/kg/day (approximately 4 times the human clinical exposure based on AUC) in males and females, respectively. The relevance of the male rat neoplastic finding to humans is unknown.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ibrance capsules.

Microcrystalline cellulose, lactose monohydrate, sodium starch glycollate, silicon dioxide and magnesium stearate.
The capsules are opaque and are differentiated by size, colour and printing. The capsule shells contain gelatin, iron oxide red, iron oxide yellow and titanium dioxide and are printed with Opacode S-1-7085 white printing ink. The capsule shells consist of a light orange body/light orange cap (75 mg), a light orange body/caramel cap (100 mg) and a caramel body/caramel cap (125 mg).

Ibrance film-coated tablets.

Tablet core: Microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate and succinic acid.
Film coating: Hypromellose, titanium dioxide, triacetin, indigo carmine aluminium lake, iron oxide red (75 mg and 125 mg tablets only), and iron oxide yellow (100 mg tablets only).
The tablets are differentiated by shape, colour and embossing. The 75 mg tablet is round shaped and light purple, the 100 mg tablet is oval shaped and green, the 125 mg tablet is oval shaped and light purple.

6.2 Incompatibilities

See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.
Ibrance tablets: store in the original blister package to protect from moisture.

6.5 Nature and Contents of Container

Ibrance 75 mg, 100 mg and 125 mg capsules are supplied in HDPE bottles or PVC/PCFTE/PVC Al blister packs containing 21 capsules.
Ibrance 75 mg, 100 mg and 125 mg film-coated tablets are supplied in PVC/OPA/Al/PVC Al blister packs containing 21 tablets.
Not all pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The chemical name of palbociclib is 6-acetyl-8- cyclopentyl-5- methyl-2-{[5-(piperazin-1-yl) pyridin-2yl] amino}pyrido[2,3-d]pyrimidin-7(8H)-one.
Its molecular formula is C24H29N7O2 which corresponds to a molecular weight of 447.54 Daltons.

Chemical structure.


Palbociclib is a yellow to orange powder with a pKa of 7.4 (secondary piperazine nitrogen) and 3.9 (pyridine nitrogen). The solubility of palbociclib in aqueous media decreases over the range pH 4.3 to pH 9.0 from greater than 0.7 mg/mL to less than 0.002 mg/mL. At or below pH 4, palbociclib behaves like a high solubility compound. Above pH 4, the solubility of the drug substance reduces significantly. The partition coefficient (1-octanol/water) at pH 7.4 is 0.99.

CAS number.

571190-30-2.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes