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.

SUMMARY CMI

IBRANCE®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using IBRANCE?

IBRANCE contains the active ingredient palbociclib. IBRANCE is used to treat advanced breast cancer.

For more information, see Section 1. Why am I using IBRANCE? in the full CMI.

2. What should I know before I use IBRANCE?

Do not use if you have ever had an allergic reaction to palbociclib or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use IBRANCE? in the full CMI.

3. What if I am taking other medicines?

Some medicines and IBRANCE may interfere with each other. It is important you tell your doctor or pharmacist if you are taking any medicines used to treat fungal or bacterial infections, HIV/AIDS infections, hepatitis C, tuberculosis, certain heart conditions or high blood pressure, epilepsy/seizures and depression and sleep disorders.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use IBRANCE?

  • IBRANCE is a tablet and is taken by mouth.
  • Your doctor will advise how much IBRANCE to use depending on your medical condition.
  • Detailed instructions on how to take IBRANCE are provided in the 'Instructions for Use' leaflet inside the pack.

More instructions can be found in Section 4. How do I use IBRANCE? in the full CMI.

5. What should I know while using IBRANCE?

Things you should do
  • Remind any doctor, pharmacist or dentist you visit that you are using IBRANCE.
  • Check with your doctor before you receive any vaccines.
  • Use a reliable method of contraception during treatment with IBRANCE.
  • It is important to tell your doctor if you get symptoms of an infection.
Things you should not do
  • Do not lower the dosage or stop using IBRANCE without checking with your doctor.
  • Do not eat grapefruit or drink grapefruit juice while you are being treated with IBRANCE.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how IBRANCE affects you.
  • The effects on your ability to drive and use machines whilst taking this medicine are not known.
Looking after your medicine
  • Keep IBRANCE in a cool dry place where the temperature stays below 30°C.
  • Keep your medicine in the pack until it is time to use it in order to protect it from light.

For more information, see Section 5. What should I know while using IBRANCE? in the full CMI.

6. Are there any side effects?

IBRANCE can make you more likely to get infections or make any infection that you may have worse.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

IBRANCE®

Active ingredient(s): Palbociclib


Consumer Medicine Information (CMI)

This leaflet provides important information about using 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 using this medicine against the benefits they expect it will have for you.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using IBRANCE.

Read this leaflet carefully before you use IBRANCE and keep it with the medicine. You may need to read it again.

Where to find information in this leaflet:

1. Why am I using IBRANCE?
2. What should I know before I use IBRANCE?
3. What if I am taking other medicines?
4. How do I use IBRANCE?
5. What should I know while using IBRANCE?
6. Are there any side effects?
7. Product details

1. Why am I using IBRANCE?

IBRANCE contains the active ingredient palbociclib. IBRANCE belongs to a group of medicines called cyclin-dependent kinase inhibitors.

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.

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.

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

2. What should I know before I use IBRANCE?

Warnings

Do not take IBRANCE if:

  1. you are allergic to palbociclib, or any of the ingredients listed at the end of this leaflet.
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.
Always check the ingredients to make sure you can use this medicine.

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.

Check with your doctor if you:

  • have had abnormal blood test results.
    Decreased numbers of white blood cells, red blood cells and platelets are very common while you are being treated with IBRANCE. Your doctor will monitor you with regular blood tests to check for changes in the levels of your blood cells.
    Low numbers of white blood cells can increase your risk of infection. Low numbers of red blood cells can increase tiredness and shortness of breath and make your skin paler than normal. Low numbers of platelets can increase your risk of bleeding.
  • have had fever, chills or any other signs or symptoms of infection.
    Patients taking IBRANCE are predisposed to infections because they very commonly experience a decrease in white blood cells which affects how well their immune system works.
  • have had a cough, shortness of breath, wheezing, dizziness or a blue tinge to your fingertips, skin or lips. Severe, life-threatening and fatal cases of pneumonitis and Interstitial Lung Disease (ILD) (inflammation of the tissues of the lungs and inflammation of the lining of cells the lungs resulting in scarring) have been reported in patients taking IBRANCE. It is important you pay attention to new or worsening symptoms that affect your breathing and tell your doctor.
  • have or have had kidney problems
  • have or have had liver problems
  • lactose intolerance
  • have allergies to any other medicines, foods, preservatives or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

IBRANCE may affect the developing baby and should not be taken during pregnancy.

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.

Tell your doctor if you are breastfeeding.

You should not breastfeed if you are being treated with IBRANCE.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and IBRANCE may interfere with each other.

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

Tell your doctor if you are taking any other medicines to treat your condition.

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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect IBRANCE.

4. How do I take IBRANCE?

IBRANCE is taken orally as a single tablet and swallowed whole.

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

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

Always take IBRANCE exactly as your doctor has instructed you.

Check with your doctor or pharmacist if you are not sure.

How much to take

Advanced Breast Cancer

  • The usual dose of IBRANCE for adults with advanced breast cancer is one 125 mg 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 change of getting side effects and could stop you getting an infection.
  • Other medicines will be prescribed by your doctor to be taken while you are being treated with IBRANCE.

How to take IBRANCE

  • IBRANCE is swallowed whole with a glass of water.
  • Do not chew, crush or split the tablets prior to swallowing.

How long to take IBRANCE

  • Keep taking IBRANCE for as long as your doctor tells you.
  • This medicine helps control your condition but does not cure it. It is important to keep taking your medicine even if you feel well.
  • Ask your doctor if you are not sure how long to take this medicine for.

If you forget to take IBRANCE 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

If you think that you have taken too much IBRANCE, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Always take the outer carton of the medicine with you.

5. What should I know while using IBRANCE?

Things you should 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.

Call your doctor straight away while taking IBRANCE if you:

  • Develop a fever
  • Become pregnant

If you are about to be started on any new medicine, tell your doctor you are using IBRANCE.

Remind any doctor, pharmacist or dentist you visit that you are using IBRANCE.

If you are going to have surgery, tell all doctors that you are taking IBRANCE. It may affect other medicines used during surgery.

Keep all your doctor's appointments so that your progress can be checked.

Things you should not do

  • Do not give IBRANCE to anyone else, even if they have the same condition as you.
  • Do not use IBRANCE to treat any other complaints unless your doctor tells you to.
  • Do not stop using IBRANCE or lower the dosage without checking with your doctor.
  • 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.

Things to be careful of

  • You might get infections, including chest infections, more easily while you are receiving IBRANCE treatment. These infections may be serious.
  • Your doctor may recommend you pause or discontinue IBRANCE treatment if you develop a severe or recurring infection, or if your blood tests show your white blood cells, red blood cells or platelets remain low for a prolonged period.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how IBRANCE affects you.

The effects on your ability to drive and use machines whilst taking this medicine are not known. 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.

Looking after your medicine

Keep your medicine in the pack until it is time to use it to protect it from light. If you take the tablets out of the pack, they may not keep well.

Keep IBRANCE 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 windowsill or in the car. Heat and dampness can destroy some medicines.

Do not use this medicine after the expiry date or if the packaging is torn or shows signs of tampering.

Keep it where children cannot reach it.

A locked cupboard at least 1.5 metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

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.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Common side effects

Common side effectsWhat to do
Blood related issues
  • Bleeding or bruising more easily than usual
  • Low white blood cell, red blood cell or platelet cell counts
Gastrointestinal issues
  • Nausea (feeling sick), diarrhoea or vomiting
  • Redness, irritation, sores or swelling of the mouth, cheeks, gums and lips
Metabolism and nutrition disorders
  • Loss of appetite
Skin related issues
  • Hair thinning or loss
  • Skin rash, dryness or redness
General disorders and administration site conditions
  • Fatigue, tiredness, lack of energy
  • Fever
  • Feeling of weakness in your muscles
Nervous system
  • Unpleasant or unusual taste in your mouth
Speak to your doctor if you have any of these more common side effects and they worry you.

They are usually mild and short-lived.

Serious side effects

Serious side effectsWhat to do
Allergic type reactions
  • Chest tightness
  • Shortness of breath, wheezing or difficulty breathing
  • Swelling of the face, lips, tongue or other parts of the body
  • Hives, itching or skin rash.
Infection issues
  • Signs and symptoms suggestive of an infection such as fever, chills, listlessness, paleness.
  • Signs and symptoms of an infection in your chest may also include discomfort in your chest, dizziness, breathlessness, rapid heart rate and weakness.
  • Signs of soft tissue infection, such as a bump or open sore that doesn't heal
Blood related issues
  • Signs and symptoms suggestive of a blood disorder such as persistent fever, bruising, bleeding very easily, paleness.
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Laboratory results

Some side effects observed with IBRANCE may not have symptoms and may only be discovered through blood tests. These include, most commonly, low levels of white blood cells and red blood cells and platelets in the blood.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What IBRANCE contains

Active ingredient
(main ingredient)
Palbociclib
Other ingredients
(inactive ingredients)

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)

Do not take this medicine if you are allergic to any of these ingredients.

What IBRANCE looks like

IBRANCE 75 mg Tablet

IBRANCE 75 mg Tablet is round, light purple, film-coated tablet debossed with “Pfizer” on one side and “PBC 75” on the other side. AUST R 319780

IBRANCE 100 mg Tablet

IBRANCE 100 mg Tablet is oval, green, film-coated tablet debossed with “Pfizer” on one side and “PBC 100” on the other side. AUST R 319782

IBRANCE 125 mg Tablet

IBRANCE 125 mg Tablet is oval, light purple, film-coated tablet debossed with “Pfizer” on one side and “PBC 125” on the other side. AUST R 319784

Each tablet blister pack contains 21 film-coated tablets.

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

Who distributes IBRANCE

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

This leaflet was prepared in June 2022.

® = Registered Trademark

Published by MIMS August 2022

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 2.3% of patients receiving palbociclib in combination with letrozole in PALOMA-2 and in 1.2% 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 7.0% and 4.3% 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 2.1% and 3.2% 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.
In patients receiving Ibrance in combination with letrozole (PALOMA-1 and PALOMA-2) and in combination with fulvestrant (PALOMA-3), ILD was reported in 1.7% and 1.4% of patients, respectively. Across PALOMA-1, PALOMA-2 and PALOMA-3 0.1% had Grade 3, and no Grade 4 or 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, dyspnoea). In patients who have new or worsening respiratory symptoms and are suspected to have developed ILD/pneumonitis, interrupt Ibrance immediately and evaluate the patient. Permanently discontinue Ibrance in patients with severe ILD or pneumonitis (see Section 4.2).
Infections. Since Ibrance has myelosuppressive properties, it may predispose to infections.
Infections of any grade have been reported at a higher rate in patients treated with Ibrance. Infections of any grade occurred in 63.6% of patients treated with Ibrance and letrozole in PALOMA-1 and PALOMA-2 compared to 42.8% of patients treated in the comparator arm. Infections of any grade occurred in 55.1% of patients treated with Ibrance and fulvestrant in PALOMA-3, compared to 36.0% of patients treated in the comparator arm.
Grade 3 and 4 infections occurred in 8.7% 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 6.1% of patients treated with Ibrance in PALOMA-3 compared to 3.5% 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, diarrhoea and thrombocytopenia.
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 81.2% of patients receiving Ibrance plus letrozole in PALOMA 1 and PALOMA-2, with grade 3 neutropenia reported in 56.2% of patients and grade 4 neutropenia reported in 12.1% 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, thrombocytopenia and vomiting.
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 84.3% of patients receiving Ibrance in combination with fulvestrant in PALOMA-3, with grade 3 neutropenia being reported in 57.7% of patients and grade 4 neutropenia being reported in 11.9% 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%).

Postmarketing experience.

The following adverse reactions have been identified during post-approval use of Ibrance. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Respiratory disorders.

Interstitial lung disease (ILD)/ pneumonitis.

Skin and subcutaneous tissue disorders.

Palmar-plantar erythrodysesthesia syndrome (PPES).

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.
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.
The results from the final OS analysis from the PALOMA-2 study are presented in Table 11. After a median follow-up time of 90 months, the final OS results were not statistically significant. The Kaplan-Meier plot of OS is shown in Figure 2.

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 12.
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 3 and Table 13.
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 4.
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 14. The relevant Kaplan-Meier plots are shown in Figures 3 and 5.
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 15.
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