Consumer medicine information

Cabazitaxel Ever Pharma

Cabazitaxel

BRAND INFORMATION

Brand name

Cabazitaxel Ever Pharma

Active ingredient

Cabazitaxel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cabazitaxel Ever Pharma.

SUMMARY CMI

CABAZITAXEL EVER PHARMA®

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 being given CABAZITAXEL EVER PHARMA?

CABAZITAXEL EVER PHARMA contains the active ingredient cabazitaxel. CABAZITAXEL EVER PHARMA is used to treat prostate cancer that has progressed after having had other chemotherapy.

For more information, see Section 1. Why am I taking CABAZITAXEL EVER PHARMA? in the full CMI.

2. What should I know before I am given CABAZITAXEL EVER PHARMA?

Do not take CABAZITAXEL EVER PHARMA if you have ever had an allergic reaction to cabazitaxel or any of the ingredients listed at the end of this CMI.

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

For more information, see Section 2. What should I know before I take CABAZITAXEL EVER PHARMA? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with CABAZITAXEL EVER PHARMA and affect how it works.

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

4. How will I be given CABAZITAXEL EVER PHARMA?

  • CABAZITAXEL EVER PHARMA will be given by infusion into one of your veins (intravenous use). The infusion will last approximately 1 hour during which you will be in the hospital.
  • The dose will depend on your height and weight. Your doctor will calculate your body surface area in square meters (m2) and will determine the dose you should receive.

More instructions can be found in Section 4. How do I take CABAZITAXEL EVER PHARMA? in the full CMI.

5. What should I know while taking CABAZITAXEL EVER PHARMA?

Things you should do
  • Remind any doctor, surgeon, dentist or pharmacist you visit that you are using CABAZITAXEL EVER PHARMA.
  • Use a condom during sex if your partner is or could become pregnant.
Things you should not do
  • Do not stop being given CABAZITAXEL EVER PHARMA without checking with your doctor.
  • Do not receive CABAZITAXEL EVER PHARMA if you are pregnant or breastfeeding.
  • Do not father a child during and up to 6 months after treatment.
Driving or using machines
  • Make sure you know how you react to CABAZITAXEL EVER PHARMA before you drive a car, operate machinery, or do anything else that could be dangerous if you feel dizzy or fatigued.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
Looking after your medicine
  • CABAZITAXEL EVER PHARMA is stored in the pharmacy or on the ward. Do not store at home.

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

6. Are there any side effects?

Serious side effects include swelling of the face, lips, mouth or throat, hives, fainting, yellowing of the skin and eyes (jaundice). Common side effects include feeling weak or lack of energy, anaemia like tiredness, inability to perform daily tasks, increased bleeding, loss of appetite, alteration in sense of taste, shortness of breath.

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

CABAZITAXEL EVER PHARMA®

Active ingredients: cabazitaxel

Consumer Medicine Information (CMI)

This leaflet provides important information about being given CABAZITAXEL EVER PHARMA. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about being given CABAZITAXEL EVER PHARMA.

Where to find information in this leaflet:

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

1. Why am I being given CABAZITAXEL EVER PHARMA?

CABAZITAXEL EVER PHARMA contains the active ingredient cabazitaxel. It belongs to a group of medicines called 'taxanes' used to treat cancers. CABAZITAXEL EVER PHARMA is used to treat prostate cancer that has progressed after having had other chemotherapy. It works by stopping cells from growing and multiplying.

There is no evidence that this medicine is addictive.

2. What should I know before I am given CABAZITAXEL EVER PHARMA?

Warnings

You must not be given CABAZITAXEL EVER PHARMA if:

  • you are allergic to cabazitaxel or any of the ingredients listed at the end of this leaflet. Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.
  • Always check the ingredients to make sure you can use this medicine.
  • you have or have had any of the following medical conditions if:
    - the number of your white blood cells is too low (neutrophil counts of 1,500 per cubic millimetre, or less - your doctor will advise you on this)
    - you have a liver disease
    - you have recently received or are about to receive a vaccine against yellow fever
    - you are pregnant or breastfeeding (see Pregnancy and Breastfeeding below)

Check with your doctor if you:

  • have allergies to:
    - any other medicines
    - aspirin or any other non-steroidal anti-inflammatory drugs (NSAID)
    - any other substances, such as foods, preservatives or dyes
  • have or have had any medical conditions, especially the following:
    - a fever (during treatment with CABAZITAXEL EVER PHARMA, it is more likely that your white blood cell count may be reduced). Your doctor will monitor your blood and general condition for signs of infections
    - any allergies
    - lung, liver or kidney problems
    - any stomach problems past or present (including ulcers)
    - severe or long-lasting diarrhoea, nausea or vomiting. Any of these events could cause dehydration. Your doctor may need to treat you
    - if you have a feeling of numbness, tingling, burning or decreased sensation in your hands or feet
    - if you have any bleeding from the gut that may cause changes in the colour of your stool or stomach pain
  • take any medicines for any other condition
  • plan to have surgery

The vial with 4.5 mL concentrate of CABAZITAXEL EVER PHARMA contains 888.8 mg ethanol 100% (25% v/v), equivalent to 22.5 mL of beer or 9.4 mL of wine.

The vial with 5 mL concentrate of CABAZITAXEL EVER PHARMA contains 987.5 mg ethanol 100% (25% v/v), equivalent to 25 mL of beer or 10.4 mL of wine.

The vial with 6 mL concentrate of CABAZITAXEL EVER PHARMA contains 1185 mg ethanol 100% (25% v/v), equivalent to 30 mL of beer or 12.5 mL of wine.

This will be taken into account if you:

  • suffer from alcoholism
  • have a liver disease
  • have epilepsy/seizures

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?

Pregnancy and breastfeeding

Do not receive CABAZITAXEL EVER PHARMA if you are pregnant or intend to become pregnant.

CABAZITAXEL EVER PHARMA may affect your developing baby if you are given CABAZITAXEL EVER PHARMA during pregnancy.

If your partner is pregnant or is planning on becoming pregnant, ensure to use a condom.

The use of effective contraception in male patients with partners who may become pregnant is recommended during treatment and for 6 months after the final treatment is given. CABAZITAXEL EVER PHARMA might be present in your semen. Therefore, the use of a condom is always recommended during sexual intercourse.

Do not receive CABAZITAXEL EVER PHARMA if you are breastfeeding or planning to breastfeed.

CABAZITAXEL EVER PHARMA could pass into breast milk and there is a possibility your baby may be affected.

Use in children

Do not give CABAZITAXEL EVER PHARMA to a child or adolescent.

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 can interfere with CABAZITAXEL EVER PHARMA including:

  • medicines used to treat bacterial, fungal or viral infections (e.g. clarithromycin, ketoconazole, rifampicin)
  • medicines used to treat seizures or epilepsy (e.g. carbamazepine, phenobarbital, phenytoin)
  • herbal remedy for depression and other conditions (St John's Wort (Hypericum perforatum)

Talk to your doctor before getting vaccinations while you are receiving CABAZITAXEL EVER PHARMA

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

4. How will I be given CABAZITAXEL EVER PHARMA?

How much will I be given

  • The dose will depend on your height and weight. Your doctor will calculate your body surface area in square meters (m2) and will determine the dose you should receive.
  • The standard dose of CABAZITAXEL EVER PHARMA is 20 mg per square metre. Your doctor may decide on an alternative dose depending on your condition.

How will I be given CABAZITAXEL EVER PHARMA

CABAZITAXEL EVER PHARMA will be given by infusion into one of your veins (intravenous use). The infusion will last approximately 1 hour during which you will be in the hospital.

You should usually receive your infusion once every 3 weeks. Each 3 week period is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need.

Additional Medicines

As part of your treatment for prostate cancer, you will also take an oral corticosteroid medicine (prednisone or prednisolone) daily.

Half an hour before you receive CABAZITAXEL EVER PHARMA, you will be given the following medications to reduce your chance of developing an allergic reaction or nausea:

  • antihistamine (diphenhydramine or equivalent)
  • corticosteroid (dexamethasone or equivalent)
  • H2 antagonist (ranitidine or equivalent)
  • anti-nausea medication (if required)

If you have any further questions about how you will receive this medicine, ask your doctor, pharmacist or nurse.

If you receive too much CABAZITAXEL EVER PHARMA

As CABAZITAXEL EVER PHARMA is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any unexpected or worrying side effects (such as fever, nausea, diarrhoea, vomiting, constipation, abdominal pain, including upper abdominal pain, indigestion, and reflux) after being given CABAZITAXEL EVER PHARMA

You should immediately:

  • phone the Poisons Information Centre
    (in Australia by calling 13 11 26; in New Zealand 0800 764 766), 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.

5. What should I know while being given CABAZITAXEL EVER PHARMA?

Things you should do

  • Use a condom while having sex if your partner is or could become pregnant.
  • Tell the doctor immediately if your partner becomes pregnant while you are being given CABAZITAXEL EVER PHARMA.
  • Seek advise on conservation of sperm prior to treatment because CABAZITAXEL EVER PHARMA may alter male fertility.
  • Tell all the doctors, dentists and pharmacists who are treating you that you are being given CABAZITAXEL EVER PHARMA.
  • If you are about to be started on any new medicine, tell your doctor and pharmacist that you are being given CABAZITAXEL EVER PHARMA.
  • If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given this medicine.

Call your doctor straight away if you:

  • have burning sensation when passing urine
  • notice anything that is making you feel unwell

Things you should not do

  • Do not father a child during and up to 6 months after treatment
  • Do not receive more than the recommended dose unless your doctor tells you to
  • Do not stop being given CABAZITAXEL EVER PHARMA without checking with your doctor

Driving or using machines

Be careful driving or operating machinery until you know how CABAZITAXEL EVER PHARMA affects you.

CABAZITAXEL EVER PHARMA may cause side effects such as fatigue or dizziness that may affect your ability to drive and use machinery. Make sure you know how you react to CABAZITAXEL EVER PHARMA before you drive a car, operate machinery, or do anything else that could be dangerous if you feel dizzy or fatigued.

If you experience these symptoms, do not drive or use any tools or machines until they have fully resolved.

Drinking alcohol

Tell your doctor if you drink alcohol or suffer from alcoholism

Looking after your medicine

CABAZITAXEL EVER PHARMA is stored in the pharmacy or on the ward. Do not store at home.

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.

Less serious side effects

Less serious side effectsWhat to do
Fatigue related:
  • feeling tired, weak or lack of energy
  • symptoms of anaemia like tiredness, and inability to perform daily tasks (due to a decrease in the number of red blood cells)
  • dizziness
Bleeding/blood related
  • increased bleeding (due to a decrease in the number of platelets)
  • blood clot in the leg
  • rectal bleeding
  • blood in the urine
  • haemorrhoids
  • decrease or increase in blood pressure
  • high blood sugar
  • low blood potassium
Pain related
  • abdominal pain
  • muscle discomfort, aches or pain
  • back pain
  • joint pain
  • pain in mouth or throat
  • sores in the mouth or on the lips
  • stomach pain
  • pain when passing urine
  • headache
  • muscle spasm
  • feeling of numbness, tingling, burning or decreased sensations in hands and feet
Infection related
  • fever and infection (associated with a reduction of white blood cells)
  • urinary tract infection
  • skin infections
  • lung infection
Inflammation related
  • Inflammation of the bladder may also occur if you have previously received radiation therapy.
  • uncomfortable feeling in the stomach or belching after eating
  • gastro-oesophageal reflux or heartburn
Allergy related
  • alteration in sense of taste
  • shortness of breath
  • redness of skin
  • skin feeling hot or flushed
  • swelling of the feet or legs
  • stomach upsets including nausea, vomiting and diarrhoea, constipation
Other
  • loss of appetite (anorexia)
  • cough
  • short term hair loss (in most cases normal hair growth should return after treatment has stopped)
  • loss of bladder control
  • rapid or irregular heartbeat
  • kidney disease or problems
  • ringing in the ear
  • trouble with balance
  • chills
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • fever (high temperature). This is very common (affects more than 1 in 10 patients)
  • severe loss of body fluids (dehydration). This is common (affects less than 1 in 10 patients). This can occur if you have severe diarrhoea (increase of more than 4 or more stools more than usual a day) or long-lasting diarrhoea, or fever, or if you are vomiting.
See a doctor immediately

Very serious side effects

Serious side effectsWhat to do
  • swelling of the face, lips, mouth or throat, which may cause difficultly in swallowing or breathing.
  • hives
  • fainting
  • yellowing of the skin and eyes (jaundice)
If you are in the hospital/clinic, tell your doctor or nurse immediately.
If you are outside of the hospital/clinic go to Accident and Emergency at your nearest hospital.

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 CABAZITAXEL EVER PHARMA contains

Active ingredients
(main ingredient)		cabazitaxel
Other ingredients
(inactive ingredients)
  • polysorbate 80
  • ethanol absolute
  • macrogol 300
  • citric acid
Potential allergensNo

CABAZITAXEL EVER PHARMA does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

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

What CABAZITAXEL EVER PHARMA looks like

CABAZITAXEL EVER PHARMA concentrate is a clear slightly yellow oily solution.

CABAZITAXEL EVER PHARMA is available in packs of:

  • one vial of 45 mg/4.5 mL
  • one vial of 50 mg/5 mL
  • one vial of 60 mg/6 mL

Australian Registration Number(s):
45 mg/4.5 mL
AUST R 320981

CABAZITAXEL EVER PHARMA
50 mg/5 mL
AUST R 320982

CABAZITAXEL EVER PHARMA
60 mg/6 mL
AUST R 321013

Who distributes CABAZITAXEL EVER PHARMA

InterPharma Pty Ltd
Suite 103
39 East Esplanade
Manly, NSW, 2095
Australia
Phone: 02 9976 6876

This leaflet was prepared in March 2021.

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Cabazitaxel Ever Pharma

Active ingredient

Cabazitaxel

Schedule

S4

 

1 Name of Medicine

Cabazitaxel.

2 Qualitative and Quantitative Composition

See Table 1.

Excipients with known effect.

Each vial of 4.5 mL concentrate contains 888.8 mg of ethanol 100%. Each vial of 5 mL concentrate contains 987.5 mg of ethanol 100%.
Each vial of 6 mL concentrate contains 1,185 mg of ethanol 100%.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrate solution for injection.
The concentrate is a clear slightly yellow oily solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Cabazitaxel Ever Pharma in combination with prednisone or prednisolone is indicated for the treatment of patients with metastatic castration resistant prostate cancer previously treated with a docetaxel containing regimen.

4.2 Dose and Method of Administration

The use of Cabazitaxel Ever Pharma should be confined to units specialised in the administration of cytotoxics and it should only be administered under the supervision of a physician experienced in the use of anticancer chemotherapy. Facilities and equipment for the treatment of serious hypersensitivity reactions like hypotension and bronchospasm must be available (see Section 4.4 Special Warnings and Precautions for Use).
Do not use PVC infusion containers (bags or bottles) for the preparation of the infusion solution.
Do not use polyurethane infusion sets (tubing, filter, pumps) for the administration of the infusion solution.

Premedication.

Premedicate at least 30 minutes prior to each administration of Cabazitaxel Ever Pharma with the following intravenous medications to reduce the risk and severity of a hypersensitivity reaction:
antihistamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent),
corticosteroid (dexamethasone 8 mg or equivalent), and
H2 antagonist (ranitidine or equivalent) (see Section 4.4 Special Warnings and Precautions for Use).
Antiemetic prophylaxis is recommended and can be given orally or intravenously as needed (see Section 4.4 Special Warnings and Precautions for Use).
Throughout the treatment, adequate hydration of the patient needs to be ensured, in order to prevent complications like renal failure.

Preparation process.

As for any other antineoplastic agent, caution should be exercised when handling and preparing Cabazitaxel Ever Pharma solutions. The use of gloves is recommended.
If Cabazitaxel Ever Pharma, at any step of its handling, should come into contact with the skin, wash immediately and thoroughly with soap and water. If it should come into contact with mucous membranes, wash immediately and thoroughly with water.
Cabazitaxel Ever Pharma should only be prepared and administered by personnel trained in handling cytotoxic agents. Pregnant staff should not handle it. Cabazitaxel Ever Pharma is for single use in one patient only. Discard any residue.
Read this entire section carefully. Cabazitaxel Ever Pharma requires one dilution step prior to administration. Follow the preparation instructions provided below.

Note.

Cabazitaxel Ever Pharma vials contain an overfill to compensate for liquid loss during preparation. The overfill ensures that the concentration in the vial will be 10 mg/mL cabazitaxel.
The following dilution process must be carried out in an aseptic manner for preparing the solution for infusion.
More than one vial of the concentrate may be necessary to administer the prescribed dose.

Dilution for infusion.

Step 1: Aseptically withdraw the required amount of concentrate (10 mg/mL of cabazitaxel), with a graduated syringe fitted with a needle. As an example, a dose of 45 mg Cabazitaxel Ever Pharma would require 4.5 mL of the concentrate.
Step 2: Inject into a sterile PVC-free container of either 5% glucose solution or 0.9% sodium chloride solution for infusion. The concentration of the infusion solution should be between 0.10 mg/mL and 0.26 mg/mL.
Step 3: Remove the syringe and mix the content of the infusion bag or bottle manually using a rocking motion.
Step 4: As with all parenteral products, the resulting infusion solution should be visually inspected prior to use. As the infusion solution is supersaturated, it may crystallise over time. In this case, the solution containing a precipitate must not be used and should be discarded.
Use an in-line filter of 0.22 micrometer (also referred to as 0.2 micrometer) nominal pore size during administration. Do not use PVC infusion containers or polyurethane infusion sets (tubing, filter, pumps) for the administration of the infusion solution.
The infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions as mentioned (see Section 6.3 Shelf Life).

Recommended dosage.

The recommended dose of Cabazitaxel Ever Pharma is 20 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone (or prednisolone) 10 mg administered daily throughout Cabazitaxel Ever Pharma treatment.
A dose of 25 mg/m2 can be used in select patients at the discretion of the treating healthcare provider (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects); Section 5.1 Pharmacodynamic Properties, Clinical trials).

Dosage adjustments.

Dosage modifications should be made if patients experience the following adverse reactions. See Table 2.
Patients at a 20 mg/m2 dose who require dose reduction should decrease dosage of Cabazitaxel Ever Pharma to 15 mg/m2 (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients at a 25 mg/m2 dose who require dose reduction should decrease dosage of Cabazitaxel Ever Pharma to 20 mg/m2.
One additional dose reduction to 15 mg/m2 may be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).
Data in patients below the 20 mg/m2 dose are limited.

Special populations.

Patients with hepatic impairment.

Cabazitaxel is extensively metabolised by the liver.
Administer Cabazitaxel Ever Pharma at a dose of 20 mg/m2 in patients with mild hepatic impairment (total bilirubin > 1 to ≤ 1.5 x Upper Limit of Normal (ULN) or AST > 1.5 x ULN). Administration of cabazitaxel to patients with mild hepatic impairment should be undertaken with caution and close monitoring of safety. Limited efficacy data for cabazitaxel at 15 mg/m2, the maximum tolerated dose in patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3.0 x ULN), are available to recommend this dose in this population (see Section 5.2 Pharmacokinetic Properties).
Cabazitaxel should not be given to patients with severe hepatic impairment (total bilirubin > 3 x Upper Limit of Normal (ULN), see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Concomitant medicinal products use.

Concomitant medicines that are strong inducers or inhibitors of CYP3A should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). However if patients require co-administration of a potent CYP3A inhibitor, a cabazitaxel dose reduction should be considered.

Patients with renal impairment.

Cabazitaxel is minimally excreted through the kidney. No dose adjustment is necessary in patients with renal impairment not requiring haemodialysis. Patients presenting end-stage renal disease (CLCR < 15 mL/min/1.73 m2) by their condition and the limited amount of available data; should be treated with caution and monitored carefully during treatment (see Section 5.2 Pharmacokinetic Properties).

Elderly.

No specific dose adjustment for the use of cabazitaxel in elderly patients is recommended (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Children.

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

4.3 Contraindications

History of severe hypersensitivity reactions to cabazitaxel, any of the excipients of cabazitaxel or other drugs formulated with polysorbate 80;
Neutrophil counts ≤ 1,500/mm3;
Severe hepatic impairment (total bilirubin > 3 x ULN);
Pregnancy and breast-feeding;
Concomitant vaccination with yellow fever vaccine (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

4.4 Special Warnings and Precautions for Use

Bone marrow suppression.

Bone marrow suppression manifested as neutropenia, anaemia, thrombocytopenia or pancytopenia may occur, (see additional information in the Neutropenia and Anaemia precautions below).

Neutropenia.

Neutropenic deaths have been reported with cabazitaxel. Neutropenia is the most common adverse reaction of cabazitaxel (see Section 4.8 Adverse Effects (Undesirable Effects)). Monitoring of complete blood count is essential on a weekly basis during cycle 1 and before each treatment cycle thereafter so that the dose can be adjusted, if needed (see Section 4.2 Dose and Method of Administration).
Dose reduction is recommended in the case of febrile neutropenia, or prolonged neutropenia despite appropriate treatment (see Section 4.2 Dose and Method of Administration).
Restart treatment only when neutrophils recover to a level > 1.5 cells x 109/L (see Section 4.3 Contraindications).
The use of G-CSF has been shown to limit the incidence and severity of neutropenia.
Patients treated with cabazitaxel may receive prophylactic G-CSF as per American Society of Clinical Oncology (ASCO) and/or current institutional guidelines, to reduce the risk or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection).
Primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features (age > 65 years, poor performance status, previous episodes of febrile neutropenia, extensive prior radiation ports, poor nutritional status, or other serious comorbidities) that predispose them to increased complications from prolonged neutropenia.

Hypersensitivity reactions.

All patients should be premedicated prior to the initiation of the infusion of cabazitaxel (see Section 4.2 Dose and Method of Administration).
Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of cabazitaxel, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe reactions can occur and may include generalised rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of cabazitaxel and appropriate therapy. Patients who have a history of severe hypersensitivity reactions should not be rechallenged with cabazitaxel (see Section 4.3 Contraindications).

Gastrointestinal symptoms.

Nausea, vomiting and severe diarrhoea may occur. A death related to diarrhoea and electrolyte imbalance occurred with cabazitaxel in the efficacy trial. Intensive measures may be required for severe diarrhoea and electrolyte imbalance. Patients should be treated with rehydration, anti-diarrhoeal or anti-emetic medications as needed. Monitor and correct serum electrolyte levels particularly potassium. Delay in cabazitaxel treatment or reduction in dose may be necessary if patients experience Grade ≥ 3 diarrhoea (see Section 4.2 Dose and Method of Administration). Diarrhoea can also occur more frequently in patients who have received prior abdomino-pelvic irradiation. Dehydration is more common in patients aged 65 or older.
Gastrointestinal (GI) haemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with cabazitaxel. Caution is advised with treatment of patients most at risk of developing gastrointestinal complications: those with neutropenia, the elderly, concomitant use of NSAIDs, antiplatelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, gastrointestinal disease, such as ulceration and GI bleeding.
Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhoea, with or without neutropenia, maybe be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary.

Peripheral neuropathy.

Cases of peripheral neuropathy, both sensory (e.g. paraesthesia, dysaesthesia) and motor, have been observed in patients treated with cabazitaxel. Patients should be advised to consult their doctor prior to continuing treatment if neuropathy symptoms such as pain, burning, tingling, numbness or weakness develop. Physicians should assess patients for the presence or worsening of neuropathy before each treatment. Treatment should be delayed until improvement of symptoms. For persistent Grade ≥ 2 peripheral neuropathy, the dose of cabazitaxel should be reduced (see Section 4.2 Dose and Method of Administration).

Urinary disorders.

Cystitis due to radiation recall phenomenon has been reported with cabazitaxel therapy in patients who have previously received pelvic radiation therapy and docetaxel containing regimen (see Section 4.8 Adverse Effects (Undesirable Effects)).
Appropriate measures should be initiated.
Interruption or discontinuation of cabazitaxel therapy may be necessary.

Respiratory disorders.

Interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome have been reported and may be associated with fatal outcome (see Section 4.8 Adverse Effects (Undesirable Effects)). If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated and appropriately treated. Interruption of cabazitaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may improve the condition. The benefit of resuming cabazitaxel treatment must be carefully evaluated.

Eye disorders.

Subcapsular lens fibre swelling/degeneration was observed in rats during a 10-cycle toxicity study at 10 mg/kg (60 mg/m2 [approximately 2-fold the AUC in cancer patients at the recommended human dose]). The No-Observable Effect Level for microscopic lens findings was 5 mg/kg (30 mg/m2 [approximately the AUC in cancer patients at the recommended human dose]). The clinical relevance of these findings is unknown. Adverse reactions were not observed in clinical studies.

Anaemia.

Anaemia has been observed in patients receiving cabazitaxel (see Section 4.8 Adverse Effects (Undesirable Effects)). Haemoglobin and haematocrit should be checked before treatment with cabazitaxel and if patients exhibit signs or symptoms of anaemia or blood loss. Caution is recommended in patients with haemoglobin < 100 g/L and appropriate measures should be taken as clinically indicated.

Risk of cardiac arrhythmias.

Cardiac arrhythmias have been reported, most commonly tachycardia and atrial fibrillation (see Section 4.8 Adverse Effects (Undesirable Effects)).

Excipients.

This medicinal product contains 197.5 mg ethanol per mL.

Vial 4.5 mL.

This medicine contains 888.8 mg of ethanol (alcohol), equivalent to 22.5 mL of beer or 9.4 mL of wine.

Vial 5 mL.

This medicine contains 987.5 mg ethanol (alcohol), equivalent to 25 mL of beer or 10.4 mL of wine.

Vial 6 mL.

This medicine contains 1185 mg ethanol (alcohol), equivalent to 30 mL of beer or 12.5 mL of wine.

Use in hepatic impairment.

Cabazitaxel is contraindicated in patients with severe hepatic impairment [total bilirubin > 3 Upper limit of Normal (ULN)] (see Section 4.3 Contraindications).
Cabazitaxel is extensively metabolised by the liver. Dose should be reduced for patients with mild (total bilirubin > 1 to ≤ 1.5 x ULN or AST > 1.5 x ULN) hepatic impairment (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Bile ductule hyperplasia, arteriolar/periarteriolar necrosis, and/or hepatocellular necrosis were observed in dogs after a single dose (0.25 mg/kg [5 mg/m2]) 5-day (0.2 mg/kg [4 mg/m2]) and weekly (0.325 mg/kg [6.5 mg/m2]) administration. Kupffer cell pigmentation and bile duct degeneration/regeneration were observed in the liver at the highest tested dose of 10 mg/kg (60 mg/m2) in a 10-cycle study in rats.

Use in renal impairment.

Cabazitaxel is minimally excreted via the kidney (2.3% of the dose excreted as the unchanged drug). No formal pharmacokinetic studies were conducted with cabazitaxel in patients with renal impairment. However, the population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
Renal disorders have been reported in association with sepsis, severe dehydration due to diarrhoea, vomiting and obstructive uropathy. Renal failure including cases with fatal outcome has been observed. Appropriate measures should be taken to identify the cause and intensively treat the patients if this occurs. Ensure adequate hydration throughout treatment with cabazitaxel. Advise the patient to report any significant change in daily urine volume immediately. Measure serum creatinine at baseline, with each blood count and whenever the patient reports a change in urinary output. Discontinue cabazitaxel in case of renal failure ≥ Grade 3.

Use in the elderly.

Elderly patients (≥ 65 years of age) may be more likely to experience certain adverse reactions including neutropenia or febrile neutropenia with cabazitaxel (see Section 4.8 Adverse Effects (Undesirable Effects)).
In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) ≥ 65 years of age died of causes other than disease progression within 30 days of the last cabazitaxel dose.
In the population pharmacokinetic analysis in 70 patients of 65 years and older (57 from 65 to 75 and 13 ≥ 75), there was no age effect on the pharmacokinetics of cabazitaxel. No specific dose adjustment is recommended in the elderly.

Paediatric use.

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

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal clinical drug-drug interaction studies have been performed.
In vitro studies have shown that cabazitaxel is mainly metabolized through CYP3A (80% to 90%).

CYP3A inhibitors.

Though no formal drug interaction trials have been conducted for cabazitaxel, concomitant administration of potent CYP3A inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) is expected to increase concentrations of cabazitaxel. Therefore, co administration with potent CYP3A inhibitors should be avoided.
If co-administration with a potent CYP3A inhibitor cannot be avoided, close monitoring for toxicity and a cabazitaxel dose reduction should be considered. Caution should be exercised with concomitant use of moderate CYP3A inhibitors.

CYP3A inducers.

Though no formal drug interaction trials have been conducted for cabazitaxel, the concomitant administration of CYP3A inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) is expected to decrease cabazitaxel concentrations. Therefore, co-administration with CYP3A inducers should be avoided (see Section 5.2 Pharmacokinetic Properties). In addition, patients should also refrain from taking St. John's Wort.
In vitro, cabazitaxel has also been shown to inhibit the transport proteins of the Organic Anion Transport Polypeptides OATP1B1. The risk of interaction with OATP1B1 substrates (e.g. statins, valsartan, repaglinide) is possible notably during the infusion duration (1 hour) and up to 20 minutes after the end of the infusion and may lead to an increase of exposure of OATP1B1 substrates.
Prednisone/prednisolone administered at 10 mg daily did not affect the pharmacokinetics of cabazitaxel.
In vitro, cabazitaxel did not inhibit Multidrug Resistant Proteins (MRP): MRP1 and MRP2. Cabazitaxel inhibited the transport of P-glycoprotein (P-gp) (digoxin, vinblastine) and Breast Cancer Resistant Proteins (BRCP) (methotrexate), at concentrations at least 37-fold what is observed in clinical settings. Therefore the risk of interaction, with MRP, P-gp and BCRP substrates, is unlikely in vivo at the dose of 20 or 25 mg/m2.

Vaccinations.

Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapy may result in serious or fatal infections. Vaccination with a live attenuated vaccine should be avoided in patients receiving cabazitaxel (see Section 4.3 Contraindications). Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effect of cabazitaxel on human fertility is unknown. Cabazitaxel did not affect mating performances or fertility of male or female rats at intravenous cabazitaxel doses of up to 0.2 mg/kg/day (resulting in AUCs below those in patients at the recommended dose). However, in multi-cycle toxicity studies following the clinically recommended dosing schedule in rats and dogs, the male reproductive system was identified as a target organ in both species and the female reproductive system was identified as a target organ in rats. Toxic effects, including seminiferous tubular atrophy and degeneration of seminal vesicles in males, and atrophy of the uterus and necrosis of corpora lutea in females, were observed at exposures (AUC) similar to or less than the AUC in patients at the recommended dose.
Animal studies showed that cabazitaxel affected the reproductive system in male rats and dogs without any functional effect on fertility. Nevertheless, considering the pharmacological activity of taxanes, their genotoxic potential and effect of several compounds of this class on fertility in animal studies, effect on male fertility could not be excluded in human.
Due to potential effects on male gametes and to potential exposure via seminal liquid, men treated with cabazitaxel should use effective contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of cabazitaxel. Due to potential exposure via seminal liquid, men treated with cabazitaxel should prevent contact with the ejaculate by another person throughout treatment. Men being treated with cabazitaxel are advised to seek advice on conservation of sperm prior to treatment.
(Category D)
Cabazitaxel is not recommended during pregnancy.
Due to potential exposure via seminal liquid, men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of cabazitaxel.
There are no adequate and well-controlled studies in pregnant women using cabazitaxel. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with cabazitaxel.
Studies in rats have shown that cabazitaxel crosses the placenta barrier. When female rats were given cabazitaxel intravenously once daily during the period of organogenesis embryofoetal toxicity was observed at a dose of 0.16 mg/kg/day, (resulting in exposures (AUC) well below those in patients at the recommended dose) consisting of foetal deaths and decreased mean foetal weight associated with a delay in skeletal ossification. Similar findings have been reported with docetaxel or paclitaxel.
Cabazitaxel did not produce foetal abnormalities in rats and rabbits.
 Cabazitaxel should not be used during breast-feeding.
Data in rats have shown excretion of cabazitaxel and/or its metabolites in milk.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed. However, based on the safety profile, cabazitaxel may have moderate influence on the ability to drive and use machines as it may cause fatigue and dizziness. Patients should be advised to not drive or use machines if they experience these adverse reactions during treatment.

4.8 Adverse Effects (Undesirable Effects)

The following Council for International Organizations of Medical Sciences (CIOMS) frequency rating is used, when applicable:
Very common ≥ 10%; Common ≥ 1 and < 10%; Uncommon ≥ 0.1 and < 1%; Rare ≥ 0.01 and < 0.1%; Very rare < 0.01%; not known (cannot be estimated from the available data).
The safety of cabazitaxel in combination with prednisone or prednisolone was evaluated in 371 patients with metastatic castration resistant prostate cancer, in a randomised open label, controlled phase III study (TROPIC). Patients received a median of 6 cycles of cabazitaxel or 4 of mitoxantrone.
The most commonly (≥ 5%) occurring Grade ≥ 3 adverse reactions in the cabazitaxel group were neutropenia (81.7%), febrile neutropenia (7.5%), diarrhoea (6.2%), leukopenia (68.2%) and anaemia (10.5%).
Discontinuation of treatment due to adverse drug reactions occurred in 68 patients (18.3%) in the cabazitaxel group and 31 patients (8.4%) in the mitoxantrone group. The most common adverse reaction leading to treatment discontinuation in the cabazitaxel group was neutropenia. See Table 3.

Neutropenia and associated clinical events.

Incidence of Grade ≥ 3 neutropenia based on laboratory data was 81.7%. The incidence of clinical neutropenia and febrile neutropenia adverse reactions were 21.3% and 7.5%, respectively. Neutropenia was the most common adverse reaction leading to drug discontinuation (2.4%). Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases resulted in a fatal outcome.
The use of G-CSF has been shown to limit the incidence and severity of neutropenia (see Section 4.4 Special Warnings and Precautions for Use).

Cardiac disorders and arrhythmias.

All Grade events among cardiac disorders were more common on cabazitaxel of which 6 patients (1.6%) had Grade ≥ 3 cardiac arrhythmias. The incidence of tachycardia on cabazitaxel was 1.6%, none of which were Grade ≥ 3. The incidence of atrial fibrillation was 1.1% in the cabazitaxel group. Cardiac failure events were more common on cabazitaxel, the event term being reported for 2 patients (0.5%). One patient in the cabazitaxel group died from cardiac failure. Fatal ventricular fibrillation was reported in 1 patient (0.3%), and cardiac arrest in 2 patients (0.5%). None were considered related by the investigator, however an indirect relationship cannot be ruled out (e.g. electrolyte imbalance).

Renal and urinary tract disorders.

Renal failure was observed at 2.2% in all grades and 1.6% in grades ≥ 3 in the cabazitaxel arm. Haematuria all grades was observed at 20.8% in EFC11785 study (see Section 5.1 Pharmacodynamic Properties, Clinical trials). Confounding causes such as disease progression, instrumentation, infection or anticoagulation/NSAID/aspirin therapy were identified in nearly two thirds of the cases.

Other laboratory abnormalities.

The incidence of Grade ≥ 3 anaemia, increased AST/SGOT, increased ALT/SGPT, and increased bilirubin based on laboratory abnormalities were 10.6%, 0.9%, 1.1%, and 0.6%, respectively.

Post marketing experience.

The following adverse reactions have been identified from clinical trials and/or post-marketing surveillance. Because they are reported from a population of unknown size, precise estimates of frequency cannot be made:

Gastrointestinal disorders.

Colitis, enterocolitis, gastritis, neutropenic enterocolitis have been observed. Gastrointestinal haemorrhage and perforation, ileus and intestinal obstruction have also been reported.

Respiratory disorders.

Cases of interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome, including cases with fatal outcomes have been reported (see Section 4.4 Special Warnings and Precautions for Use).

Renal and urinary disorders.

Cystitis due to radiation recall phenomenon was reported uncommonly (see Section 4.4 Special Warnings and Precautions for Use).

Elderly population.

Of the 371 patients treated with cabazitaxel in the prostate cancer study, 240 patients were 65 years or over including 70 patients older than 75 years. The following adverse reactions reported at rates ≥ 5% higher in patients 65 years of age or greater compared to younger patients were: fatigue (40.4% vs. 29.8%), clinical neutropenia (24.2% vs. 17.6%), asthenia (23.8% vs. 14.5%), pyrexia (14.6% vs. 7.6%), dizziness (10.0% vs. 4.6%), urinary tract infection (9.6% vs 3.1%) and dehydration (6.7% vs. 1.5%), respectively.
The incidence of the following Grade ≥ 3 adverse reactions were higher in patients ≥ 65 years of age compared to younger patients: neutropenia based on laboratory abnormalities (86.3% vs. 73.3%), clinical neutropenia (23.8% vs. 16.8%) and febrile neutropenia (8.3% vs. 6.1%) (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly). Of the 595 patients treated with cabazitaxel 25 mg/m2 in the prostate cancer EFC 11785 study, 420 patients were 65 years or over. The adverse reactions reported at rates of at least 5% higher in patients 65 years of age or greater compared to younger patients were diarrhoea (42.9% vs. 32.6%), fatigue (30.2% vs. 19.4%), asthenia (22.4% vs. 13.1%), constipation (20.2% vs. 12.6%), clinical neutropenia (12.9% vs. 6.3%), febrile neutropenia (11.2% vs. 4.6%) and dyspnoea (9.5% vs. 3.4%).

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

Signs and symptoms.

The anticipated complications of overdose would be exacerbation of adverse reactions such as bone marrow suppression and gastrointestinal disorders.

Management.

There is no known antidote to cabazitaxel. In case of overdose, the patient should be kept in a specialised unit and closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Class.

Antineoplastic agent ATC code: L01CD04.

Mechanism of action.

Cabazitaxel is an antineoplastic agent that acts by disrupting the microtubular network in cells. Cabazitaxel binds to tubulin and promotes the assembly of tubulin into microtubules while simultaneously inhibiting their disassembly. This leads to the stabilisation of microtubules, which results in the inhibition of mitotic and interphase cellular functions.
Cabazitaxel demonstrated a broad spectrum of antitumor activity against advanced human tumours xenografted in mice, including intracranial human glioblastomas.
Cabazitaxel is active in docetaxel-sensitive tumours. In addition cabazitaxel demonstrated activity in some tumour models insensitive to chemotherapy, including docetaxel.

Clinical trials.

The efficacy and safety of cabazitaxel in combination with prednisone or prednisolone were evaluated in a randomised, open-label, international, multi-centre, phase III study (TROPIC), in patients with metastatic castration resistant prostate cancer previously treated with a docetaxel-containing regimen.
Overall survival (OS) was the primary efficacy endpoint of the study. Secondary endpoints included Progression Free Survival [PFS (defined as time from randomisation to tumour progression, Prostatic Specific Antigen (PSA) progression, pain progression, or death due to any cause, whichever occurred first], Tumour Response Rate based on Response Evaluation Criteria in Solid Tumours (RECIST), PSA Progression (defined as a ≥ 25% increase or ≥ 50% in PSA non-responders or responders respectively), PSA response (declines in serum PSA levels of at least 50%), pain progression [assessed using the Present Pain Intensity (PPI) scale from the McGill-Melzack questionnaire and an Analgesic Score (AS)] and pain response (defined as 2 point greater reduction from baseline median PPI with no concomitant increase in AS, or reduction of ≥ 50% in analgesic use from baseline mean AS with no concomitant increase in pain).
A total of 755 patients were randomized to receive either cabazitaxel 25 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=378), or to receive mitoxantrone 12 mg/m2 intravenously every 3 weeks for a maximum of 10 cycles with prednisone or prednisolone 10 mg orally daily (n=377).
This study included patients over 18 years with metastatic castration resistant prostate cancer either measurable by RECIST criteria or non-measurable disease with rising PSA levels or appearance of new lesions, and Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Patients had to have neutrophils > 1.5 cells x 109/L, platelets > 100 cells x 109/L, haemoglobin > 100 g/L, creatinine < 1.5 x ULN, total bilirubin < 1 x ULN, AST/SGOT < 1.5 ULN, and ALT/SGPT < 1.5 ULN.
Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.
Demographics, including age, race, and ECOG performance status (0 to 2), were balanced between the treatment arms. In the cabazitaxel group, the mean age was 68 years range (46 to 92) and the racial distribution was 83.9% Caucasian, 6.9% Asian, 5.3% Black, and 4% Others.
The median number of cycles was 6 in the cabazitaxel group and 4 in the mitoxantrone group. The number of patients who completed the study treatment (10 cycles) was 29.4% in the cabazitaxel group and 13.5% in the comparator group.
Overall survival was significantly longer with cabazitaxel compared to mitoxantrone (15.1 months versus 12.7 months, respectively), with a 30% reduction in the risk of death compared to mitoxantrone (see Table 4 and Figure 1).
See Table 5.
There were no significant differences in pain progression or pain response between treatments.
In a non-inferiority, multicentre, multinational, randomised, open label phase III study (EFC11785 study), 1200 patients with metastatic castration resistant prostate cancer, previously treated with a docetaxel containing regimen, were randomized to receive either cabazitaxel 25 mg/m2 (n=602) or 20 mg/m2 (n=598) dose. Overall survival (OS) was the primary efficacy end-point.
The study met its primary objective of demonstrating the non-inferiority of cabazitaxel 20 mg/m2 in comparison with 25 mg/m2 (see Table 6). A statistically significantly higher percentage (p < 0.001) of patients showed a PSA response in the 25 mg/m2 group (42.9%) compared to the 20 mg/m2 group (29.5%). A statistically significantly higher risk of PSA progression in patients with the 20 mg/m2 dose with respect to the 25 mg/m2 dose was observed (HR 1.195; 95%CI: 1.025 to 1.393). There was no statistically difference with regards to the other secondary endpoints (PFS, tumour and pain response, tumour and pain progression, and four subcategories of FACT-P). See Table 6.
EFC11785 study demonstrated a better safety profile for the cabazitaxel 20 mg/m2 dose. The safety profile of cabazitaxel 25 mg/m2 observed in this study was qualitatively and quantitatively similar to that observed in the study EFC6193. The patients in the 20 mg/m2 group received a median of 6 cycles (median duration of 18 weeks), while patients in the 25 mg/m2 group received a median of 7 cycles (median duration of 21 weeks). In the 25 mg/m2 group, 128 patients (21.5%) had a dose reduced from 25 to 20 mg/m2, 19 patients (3.2%) had a dose reduced from 20 to 15 mg/m2 and 1 patient (0.2%) had a dose reduced from 15 to 12 mg/m2. In the 20 mg/m2 group, 58 patients (10.0%) had a dose reduced from 20 to 15 mg/m2 and 9 patients (1.6%) had a dose reduced from 15 to 12 mg/m2. All grade adverse reactions with an incidence higher than 10% were higher in patients treated at 25 mg/m2 than in patients treated at 20 mg/m2. See Table 7.
Grade ≥ 3 adverse reactions with an incidence higher than 5% were observed in patients treated at 25 mg/m2 only. See Table 8.
There were fewer reported hematology abnormalities for patients treated at 20 mg/m2 compared with patients treated at 25 mg/m2 based on laboratory values (see Table 9):

5.2 Pharmacokinetic Properties

A population pharmacokinetic analysis was carried out in 170 patients including patients with advanced solid tumours (n=69), metastatic breast cancer (n=34) and metastatic prostate cancer (n=67). These patients received doses of cabazitaxel ranging from 10 to 30 mg/m2 weekly or every 3 weeks.

Absorption.

After a 1-hour IV administration dose of cabazitaxel at 25 mg/m2, in patients with metastatic prostate cancer (n=67), the mean Cmax was 226 nanogram/mL (coefficient of variation, CV 107%) and was reached at the end of the 1-hour infusion (Tmax). The mean AUC was 991 nanogram.h/mL (CV: 34%).
No major deviation to the dose proportionality was observed from 10 to 30 mg/m2 in patients with advanced solid tumours (n=126).

Distribution.

The volume of distribution (Vss) was 4870 L (2640 L/m2 for a patient with a median BSA of m2) at steady state.
In vitro, the binding of cabazitaxel to human serum proteins was 89% to 92% and was not saturable up to 50,000 nanogram/mL, which covers the maximum concentration observed in clinical studies. Cabazitaxel is mainly bound to human serum albumin (82.1%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). The in vitro blood-to-plasma concentration ratios in human blood ranged from 0.90 to 0.99 indicating that cabazitaxel was equally distributed between blood and plasma.

Metabolism.

Cabazitaxel is extensively metabolised in the liver (≥ 95%), mainly by the CYP3A4 isoenzyme (80% to 90%). Cabazitaxel is the main circulating compound in human plasma. Seven metabolites were detected in plasma (including 3 active metabolites issued from O-demethylation), with the main one accounting for approximately 5% of the parent exposure. Around 20 metabolites of cabazitaxel are excreted into human urine and faeces.
Based on in vitro studies, the potential risk of inhibition by cabazitaxel at clinically relevant concentrations is possible towards drugs that are mainly substrates of CYP3A. However, there is no potential risk of inhibition of drugs that are substrates of other CYP enzymes (1A2, 2B6, 2C9, 2C8, 2C19, 2E1, and 2D6) as well as no potential risk of induction by cabazitaxel on drugs that are substrates of CYP1A, CYP2C9, and CYP3A.
Potent CYP3A inducers or inhibitors could affect cabazitaxel, as cabazitaxel is mainly metabolised by CYP3A.

Excretion.

After a 1-hour IV infusion [14C]-cabazitaxel at 25 mg/m2 in patients, approximately 80% of the administered dose was eliminated within 2 weeks. Cabazitaxel is mainly excreted in the faeces as numerous metabolites (76% of the dose); while renal excretion of cabazitaxel and metabolites account for less than 4% of the dose (2.3% as unchanged drug in urine).
Cabazitaxel has a high plasma clearance of 48.5 L/h (26.4 L/h/m2 for a patient with a median BSA of 1.84 m2) and a long terminal half-life of 95 hours.
Cabazitaxel is minimally excreted via the kidney (2.3% of the dose excreted as the unchanged drug). No formal pharmacokinetic studies were conducted with cabazitaxel in patients with renal impairment. However, the population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use).

Hepatic impairment.

Cabazitaxel is eliminated primarily via hepatic metabolism. A dedicated study in 43 cancer patients with hepatic impairment showed no influence of mild (total bilirubin > 1 to ≤ 1.5 x ULN or AST > 1.5 x ULN) or moderate (total bilirubin > 1.5 to ≤ 3.0 x ULN) hepatic impairment on cabazitaxel pharmacokinetics. The maximum tolerated cabazitaxel dose (MTD) was 20 and 15 mg/m2, respectively. In 3 patients with severe hepatic impairment (total bilirubin > 3 x ULN), a 39% decrease in clearance was observed when compared to patients with mild hepatic impairment, indicating some effect of severe hepatic impairment on cabazitaxel pharmacokinetics. The MTD of cabazitaxel in patients with severe hepatic impairment was not established.
Based on safety and tolerability data, cabazitaxel dose should be reduced in patients with mild hepatic impairment (see Section 4.2 Dose and Method of Administration). Cabazitaxel is contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).

Renal impairment.

Cabazitaxel is minimally excreted via the kidney (2.3% of the dose). A population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 mL/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 mL/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of cabazitaxel. This was confirmed by a dedicated comparative pharmacokinetic study in solid cancer patients with normal renal function (8 patients), moderate (8) and severe (9) renal impairment, who received several cycles of cabazitaxel in single IV infusion up to 25 mg/m2.

5.3 Preclinical Safety Data

Genotoxicity.

Cabazitaxel was negative in the bacterial reverse mutation (Ames) test. Cabazitaxel was not clastogenic in an in vitro test in human lymphocytes (no induction of structural chromosomal aberrations) but it increased number of polyploid cells and it induced an increase of micronuclei in the in vivo micronucleus test in rats. However, these genotoxicity findings are inherent to the pharmacological activity of the compound (inhibition of tubulin depolymerisation) and have been observed with other compounds with the same pharmacological activity.

Carcinogenicity.

Long-term animal studies have not been performed to evaluate the carcinogenic potential of cabazitaxel.

6 Pharmaceutical Particulars

6.1 List of Excipients

Polysorbate 80, ethanol absolute, macrogol 300 and citric acid.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned (see Section 6.6 Special Precautions for Disposal).
PVC infusion containers or polyurethane infusion sets should not be used for the preparation and administration of the infusion solution.

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.

After opening.

Stability of the concentrate in the vial: Chemical, physical and microbiological stability of the solution after first opening has been demonstrated for 28 days at ambient temperature.

After dilution in the infusion bag/bottle.

After final dilution in the infusion bag/bottle, the infusion solution may be stored up to 8 hours below 30°C (including the 1 hour infusion).
To reduce microbiological hazard, use as soon as practicable after dilution. If storage is necessary, the infusion solution may be stored for up to 8 hours below 30°C (including the 1 hour infusion) or for not more than 24 hours at 2°-8°C.
As the infusion solution is supersaturated, it may crystallise over time. In this case, the infusion solution must not be used and should be discarded.

6.4 Special Precautions for Storage

Store below 30°C. Do not freeze. Do not refrigerate undiluted cabazitaxel concentrate.

6.5 Nature and Contents of Container

One pack contains one vial of concentrate:

45 mg/4.5 mL.

4.5 mL of concentrate containing 45 mg cabazitaxel in a 5 mL clear glass vial (type I) closed with a grey bromobutyl rubber stopper sealed by an aluminium cap covered with an aquaplastic flip-off cap.

50 mg/5 mL.

5 mL of concentrate containing 50 mg cabazitaxel in a 5 mL clear glass vial (type I) closed with a grey bromobutyl rubber stopper sealed by an aluminium cap covered with a red plastic flip-off cap.

60 mg/6 mL.

6 mL of concentrate in a 60 mg cabazitaxel in a 5 mL clear glass vial (type I) closed with a grey bromobutyl rubber stopper sealed by an aluminium cap covered with a yellow plastic flip-off cap.
An overfill of 10.8% is used for the 45 mg/4.5 mL and 50 mL/5.0 mL presentations and an overfill of 10.7% is used for the 60 mL/6.0 mL presentation.
Vials are sheathed in a protective sleeve.
Not all pack sizes may be marketed.

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

Description.

Cabazitaxel is a white to off-white powder. It is lipophilic, practically insoluble in water and soluble in alcohol.

Chemical structure.

Cabazitaxel belongs to the taxanes class. It is prepared by semi synthesis with a precursor extracted from yew needles.
Chemical name: (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3- [(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)- 1-hydroxy-7,10-dimethoxy-9-oxo-5,20- epoxytax-11-en-2-yl benzoate.
The empirical formula of cabazitaxel is C45H57NO14,C3H6O. The chemical structure of cabazitaxel is:

CAS number.

183133-96-2 (solvent free form of cabazitaxel).

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).