Consumer medicine information

DBL Docetaxel Concentrated Injection

Docetaxel

BRAND INFORMATION

Brand name

DBL Docetaxel Concentrated Injection

Active ingredient

Docetaxel

Schedule

What is in this leaflet

This leaflet answers some common questions about DBL Docetaxel, Concentrated Injection.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking DBL Docetaxel, Concentrated Injection against the benefits they expect it will have for you.

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

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

What DBL Docetaxel, Concentrated Injection is used for

Docetaxel is used to treat:

breast cancer
non small cell lung cancer
ovarian cancer
prostate cancer
head and neck cancer

This medicine belongs to a group of medicines called antineoplastic or cytotoxic medicines. You may also hear of these being called chemotherapy medicines.

It works by stopping cells from growing and multiplying.

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.

This medicine is not addictive.

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

You may have taken another medicine to treat your breast, non small cell lung cancer, ovarian, prostate or head and neck cancer. However, your doctor has now decided to treat you with docetaxel.

There is not enough information to recommend the use of this medicine for children.

Before you are given DBL Docetaxel, Concentrated Injection

When you must not be given it

Do not use DBL Docetaxel, Concentrated Injection if you have an allergy to:

any medicine containing docetaxel or polysorbate 80
any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing or a tight feeling in your chest
swelling of the face, lips, tongue or other parts of the body
rash, itching, hives or flushed, red skin
dizziness or light-headedness
back pain

Do not use DBL Docetaxel, Concentrated Injection if you have, or have had, any of the following medical conditions:

severe liver problems
blood disorder with a reduced number of white blood cells

Females: Do not use this medicine if you are pregnant or intend to become pregnant.

If you become pregnant during treatment or think you might be pregnant, speak to your doctor as soon as possible.

You should use a reliable method of contraception during treatment with DBL Docetaxel Injection and for at least 6 months after your last dose.

Like most medicines used to treat cancer, docetaxel is not recommended for use during pregnancy, unless you and your doctor have discussed the risks and benefits involved.

Do not breast-feed during treatment with this medicine and for 1 week after your last dose. It is not known if docetaxel passes into breast milk and there is a possibility that your baby may be affected.

Males: You should use a reliable method of contraception during treatment with DBL Docetaxel Injection and for at least 3 months after your last dose, if you are with a female partner who is able to become pregnant.

You should seek advice from your doctor on preserving sperm before starting treatment.

Both males and females should discuss the need for individual genetic counselling with their doctor if you decide to have a child after treatment.

Docetaxel may alter fertility in males and females.

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

Before you are given it

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

Docetaxel is not recommended for use in children. Safety and effectiveness in children have not been established.

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

blood disorder with a reduced number of white blood cells
hearing problems
heart problems
high uric acid levels
kidney problems
liver problems

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell him/her before you start using DBL Docetaxel, Concentrated Injection.

Taking other medicines

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

Some medicines and DBL Docetaxel, Concentrated Injection may interfere with each other. These include:

other medicines used to treat cancer, radiation therapy or any other treatment which lowers your immune system, including cyclosporin
some medicines used to treat bacterial infections, including erythromycin, clarithromycin and telithromycin.
Ketoconazole, itraconazole and voriconazole, medicines used to treat fungal infections
nifedipine, a medicine used to treat high blood pressure and angina
some medicines called corticosteroids
medicines used to treat people with epilepsy, such as phenobarbitone
medicines used to treat or prevent HIV or Hepatitis C viral infections, such as ritonavir, indinavir, nelfinavir and saquinavir.
medicines used to treat people with depression such as nefazodone

These medicines may be affected by DBL Docetaxel, Concentrated Injection or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

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

How DBL Docetaxel, Concentrated Injection is given

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

Docetaxel should only be administered by trained professionals, with appropriate handling, in a hospital or clinic environment.

Before you are given your docetaxel infusion your doctor should:

prescribe you an oral corticosteroid (eg dexamethasone) to help stop or reduce the severity of certain side effects. For breast, lung, ovarian and head and neck cancer, this medicine is usually taken for three days (one day before, the day of and the day after your infusion). These medicines are very important. For prostate cancer, this is usually taken on the day of the infusion (12 hours, 3 hours and 1 hour before your infusion).
test your blood to see how many white blood cells you have. If they are too low, your infusion may be delayed.
test your blood for levels of liver enzymes. If these levels are high your doctor may reduce your dose or decide you should not have a docetaxel infusion at that time.

Ask your doctor or pharmacist if you have any questions on these medicines or tests.

How much is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight, kidney function and other chemotherapy medicines you are being given.

The usual dose of docetaxel is 75 to 100mg/m² which is based on your body size (m²).

When docetaxel is given in combination with capecitabine (another medicine used for the treatment of breast cancer) the usual dose of docetaxel is 75 mg/m².

Docetaxel may be given alone or in combination with other drugs.

Several courses of docetaxel therapy may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

Ask your doctor if you want to know more about the dose of docetaxel you receive.

How it is given

DBL Docetaxel, Concentrated Injection is given as an infusion (drip) into your veins, over 1 hour.

How long it is given for

Docetaxel is given every 3 weeks. This is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need.

If you take too much (overdose)

As DBL Docetaxel, Concentrated Injection 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 severe side effects after being given DBL Docetaxel, Concentrated Injection, tell your doctor immediately or go to Accident and Emergency at the nearest hospital. You may need urgent medical attention.

In case of overdose, immediately contact the Poisons Information Centre 13 11 26

While you are using DBL Docetaxel, Concentrated Injection

Things you must do

Keep follow up appointments with your doctor. It is important to have your follow-up doses/cycles/infusions of docetaxel at the appropriate times to get the best effects from your treatments.

Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

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

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are having DBL Docetaxel, Concentrated Injection.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are having docetaxel.

If you become pregnant while having docetaxel, tell your doctor immediately.

DBL Docetaxel, Concentrated Injection can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding.

The following precautions should be taken to reduce your risk of infection or bleeding:

Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain or find it painful or difficult to urinate.

Be careful when using a toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.

Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters.

Avoid contact sports or other situations where you may bruise or get injured.

If you notice swelling in the feet and legs or a slight weight gain, inform your doctor or nurse. Docetaxel may cause fluid retention which means the body is holding extra water. If this fluid retention is in the chest or around the heart it can be life threatening. In most cases, fluid retention will go away within weeks or months after your treatments are completed.

Things you must not do

Do not use DBL Docetaxel, Concentrated Injection to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery until you know how DBL Docetaxel, Concentrated Injection affects you. Docetaxel may cause dizziness, light-headedness, tiredness, drowsiness in some people. Make sure you know how you react to docetaxel before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking DBL Docetaxel, Concentrated Injection.

It helps most people with breast, non small cell lung cancer, ovarian, prostate or head and neck cancer, but it may have unwanted side effects in a few people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

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

If you are over 60 years of age you may have an increased chance of getting side effects.

Ask your doctor or pharmacist to answer any questions you may have.

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

irritation, pain, swelling or colouring around the needle during infusion
high temperature
stomach pain or discomfort
feeling sick, upset stomach or vomiting
mild diarrhoea
constipation
inflammation of the food pipe (oesophagus)
whitening or darkening of the skin or nails
loosening of the nails
unusual hair loss or thinning
joint pain or swelling
aching muscles, muscle tenderness, swelling or weakness not caused by exercise
unusual tiredness or weakness
mild swelling of hands, ankles and feet
weight gain/loss
pins and needles or a burning or tingling feeling in hands or feet
redness or rash around previous radiation site (if you have had radiotherapy)
back pain
decreased appetite
high blood pressure (hypertension)
low blood pressure (hypotension)
temporary visual disturbances, or feeling that you are about to faint, which mostly occur when you are being infused with docetaxel.

The above list includes the more common side effects of your medicine.

Tell your doctor as soon as possible if you notice any of the following:

infections
frequent infections with fever, severe chills, sore throat or mouth ulcers - especially 5-7 days after receiving a docetaxel infusion
sore red mouth or vagina or swelling in these areas
severe diarrhoea
tiredness, headaches, being short of breath when exercising, dizziness and looking pale
coughing
change in the rhythm or rate of your heart beats (palpitations)
muscle pain or cramps
flushed, dry skin, irritability and confusion
passing little or no urine, drowsiness, nausea, vomiting and breathlessness
yellowing of the skin or eyes, also called jaundice
flaking of the skin
red, scaly patches of the skin especially around the cheeks and nose
raised lumps on the skin which looks like scalding
hardening of the skin
excessive watery discharge from the eyes
trouble with your hearing, or some loss of hearing
sudden and severe swelling or pain in the joints or rash.
Blurry or "wavy" vision or disturbances to colour vision.
Widening and rounding of the tips of the fingers or toes (clubbing).
Leg pain, tenderness or swelling.
Skin that is red and warm.

The above list includes serious side effects that may require medical attention.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

sudden signs of allergy such as rash, itching, hives on the skin, swelling of the face, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
Redness of the skin studded with pimples containing fluid or pus
convulsions, fits or seizures
hallucinations or delirium
ulcer in the stomach or intestine - vomiting blood or material that looks like coffee grounds, bleeding from the back passage, black sticky bowel motions or bloody diarrhoea
difficulty in breathing, rapid and/or shallow breathing
sudden swelling of the leg/arm which may be due to blood clots
pain, pressure or tightness in the chest, arms, neck, jaw or back that may occur together with nausea, dizziness or cold sweats
fainting
fever with diarrhoea and or vomiting, painful cramping.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

These side effects may differ when using docetaxel in combination with another chemotherapy agent.

Please consult your doctor for possible side effects that may be caused by using docetaxel with another chemotherapy agent.

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

The benefits and side effects of docetaxel may take some time to occur. Therefore, even after you have finished your docetaxel treatment you should tell your doctor immediately if you notice any of the side effects listed in this section.

After using DBL Docetaxel, Concentrated Injection

Storage

DBL Docetaxel, Concentrated Injection will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, protected from light, where the temperature stays below 25°C.

Product description

What it looks like

DBL Docetaxel, Concentrated Injection in single dose vials is a clear, colourless to pale yellow solution, which is diluted prior to intravenous administration.

Ingredients

Active ingredients:

DBL Docetaxel, Concentrated Injection contains 10mg/mL of docetaxel as the active ingredient.

Inactive Ingredients

It also contains:

ethanol
citric acid
Polysorbate 80
Macrogol 300

DBL Docetaxel, Concentrated Injection does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Sponsor

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

DBL Docetaxel, Concentrated Injection is available in the following strengths:

20 mg/2 mL vials
AUST R 163802
80 mg/8mL vials
AUST R 163801
160 mg/16mL vials
AUST R 163803

™ = Trademark

This leaflet was prepared in July 2023.

Published by MIMS September 2023

BRAND INFORMATION

Brand name

DBL Docetaxel Concentrated Injection

Active ingredient

Docetaxel

Schedule

1 Name of Medicine

Docetaxel.

2 Qualitative and Quantitative Composition

Each 1 mL DBL Docetaxel Concentrated Injection contains 10 mg docetaxel and it is supplied as a 20 mg/2 mL, 80 mg/8 mL and 160 mg/16 mL concentrated injection vial.

Excipients with known effect.

Ethanol (see Section 4.4 Special Warnings and Precautions for Use, Alcohol content).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Injection.
DBL Docetaxel Concentrated Injection is a sterile clear, colourless to pale yellow solution free from visible particulates. It must be diluted prior to intravenous administration.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Docetaxel Concentrated Injection is indicated for:

Breast cancer.

Metastatic breast cancer.

Treatment of patients with locally advanced or metastatic breast cancer in whom previous chemotherapy has failed.
DBL Docetaxel Concentrated Injection in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of prior anthracycline containing chemotherapy.
DBL Docetaxel Concentrated Injection in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2 and who previously have not received chemotherapy for metastatic disease.

Adjuvant treatment of breast cancer.

DBL Docetaxel Concentrated Injection in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with node positive breast cancer.
Doxorubicin and cyclophosphamide followed by DBL Docetaxel Concentrated Injection in combination with trastuzumab (AC-TH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2.
DBL Docetaxel Concentrated Injection in combination with carboplatin and trastuzumab (TCH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2.
DBL Docetaxel Concentrated Injection in combination with cyclophosphamide is indicated for the adjuvant treatment of operable breast cancer with a primary tumour of ≥ 1 cm and < 7 cm.

Non-small cell lung cancer.

Treatment of patients with locally advanced or metastatic non-small cell lung cancer, including those who have failed platinum-based chemotherapy.

Ovarian cancer.

Treatment of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.

Prostate cancer.

Treatment of patients with androgen independent (hormone refractory) prostate cancer.

Head and neck cancer.

DBL Docetaxel Concentrated Injection in combination with cisplatin and fluorouracil (TPF), is indicated as induction treatment prior to chemoradiotherapy, for the treatment of patients with locally advanced, squamous cell carcinoma of the head and neck, who have low probability of surgical cure, require organ preservation or where the tumour is technically unresectable.

4.2 Dose and Method of Administration

Dosage.

Breast cancer. Metastatic breast cancer.

Monotherapy.

The recommended dosage of DBL Docetaxel Concentrated Injection is 75 to 100 mg/m² administered as a one-hour infusion every three weeks (see Preparation and storage of the infusion solution). A dose of 100 mg/m² of docetaxel has been shown to result in a moderate increase in response rates compared with 75 mg/m² but is associated with greater toxicity.

Combination with capecitabine.

The recommended dosage of DBL Docetaxel Concentrated Injection is 75 mg/m² administered as a one-hour infusion every three weeks when combined with capecitabine administered orally at 1,250 mg/m² twice daily (within 30 minutes after the end of a meal) for two weeks followed by a 1-week rest period, given as 3-week cycles. Refer to capecitabine product information for capecitabine dose calculation according to body surface area.

Combination with trastuzumab (HER2+).

For the docetaxel plus trastuzumab combination, the recommended DBL Docetaxel Concentrated Injection dose is 100 mg/m² every three weeks, with trastuzumab administered weekly. For trastuzumab dosage and administration, see the trastuzumab product information leaflet.
Adjuvant treatment of breast cancer.

Combination with doxorubicin and cyclophosphamide.

The recommended dose of DBL Docetaxel Concentrated Injection in the adjuvant treatment of breast cancer is 75 mg/m² administered 1 hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for a total of six cycles (TAC regimen) (also see Dosage adjustments during treatment; see Section 4.4 Special Warnings and Precautions for Use).

Combination with trastuzumab following doxorubicin and cyclophosphamide (HER2+). AC-TH.

AC (cycles 1-4): doxorubicin (A) 60 mg/m² followed by cyclophosphamide (C) 600 mg/m² administered every three weeks for 4 cycles.
TH (cycles 5-8): docetaxel (T) 100 mg/m² administered every three weeks for 4 cycles, and trastuzumab (H) administered weekly according to the following schedule:
Cycle 5 (starting three weeks after the last cycle of AC). Day 1: trastuzumab 4 mg/kg (loading dose); day 2: docetaxel 100 mg/m²; days 8 and 15: trastuzumab 2 mg/kg.
Cycles 6-8. Day 1: docetaxel 100 mg/m² and trastuzumab 2 mg/kg; days 8 and 15: trastuzumab 2 mg/kg.
Three weeks after day 1 of cycle 8: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.

Combination with carboplatin and trastuzumab (HER2+). TCH.

TCH (cycles 1-6): docetaxel (T) 75 mg/m² and carboplatin (C) at AUC of 6 mg/mL/min administered every three weeks and trastuzumab (H) administered weekly according to the following schedule:
Cycle 1. Day 1: trastuzumab 4 mg/kg (loading dose); day 2: docetaxel 75 mg/m² and carboplatin at AUC of 6 mg/mL/min; days 8 and 15: trastuzumab 2 mg/kg.
Cycles 2-6. Day 1: docetaxel 75 mg/m² followed by carboplatin at AUC of 6 mg/mL/min and trastuzumab 2 mg/kg; days 8 and 15: trastuzumab 2 mg/kg.
Three weeks after day 1 of cycle 6: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.

Combination with cyclophosphamide.

The recommended dosage of DBL Docetaxel Concentrated Injection is 75 mg/m² over 1 hour and cyclophosphamide 600 mg/m² as an intravenous administration over 30 to 60 minutes on day 1 of a 21-day cycle for a total of four cycles. Premedication with oral dexamethasone 8 mg twice daily is administered commencing 1 day before administering DBL Docetaxel Concentrated Injection, and continuing for a total of five doses.
Non-small cell lung cancer. The recommended dosage of DBL Docetaxel Concentrated Injection is 75 to 100 mg/m² administered as a one-hour infusion every three weeks (see Preparation and storage of the infusion solution). A dose of 100 mg/m² of docetaxel has been shown to result in a moderate increase in response rates compared with 75 mg/m² but is associated with greater toxicity.
Ovarian cancer. The recommended dosage of DBL Docetaxel Concentrated Injection is 75 to 100 mg/m² administered as a one hour infusion every three weeks (see Preparation and storage of the infusion solution). A dose of 100 mg/m² of docetaxel has been shown to result in a moderate increase in response rates compared with 75 mg/m² but is associated with greater toxicity.
Prostate cancer.

Metastatic castration-resistant prostate cancer.

The recommended dosage of DBL Docetaxel Concentrated Injection for prostate cancer is 75 mg/m² administered as a one hour infusion every three weeks. Prednisone or prednisolone 5 mg orally twice daily is administered continuously, commencing day 1 and continuing through each cycle.
Head and neck cancer. Patients must receive premedication with antiemetics and appropriate hydration (prior to and after cisplatin administration). Prophylaxis for neutropenic infections should be administered. For cisplatin and fluorouracil dose modifications, see manufacturers' product information.

Induction chemotherapy followed by radiotherapy (TAX 323).

For the induction treatment of locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of DBL Docetaxel Concentrated Injection is 75 mg/m² as a one-hour infusion followed by cisplatin 75 mg/m² over one hour on day 1, followed by fluorouracil as a continuous infusion at 750 mg/m²/day for five days. This regimen is administered every three weeks for four cycles. Following chemotherapy, patients should receive radiotherapy.

Induction chemotherapy followed by chemoradiotherapy (TAX 324).

For the induction treatment of patients with locally advanced (unresectable, low surgical cure or organ preservation) SCCHN, the recommended dose of DBL Docetaxel Concentrated Injection is 75 mg/m² as a one-hour IV infusion on day 1, followed by cisplatin 100 mg/m² administered as a 30-minute to three-hour infusion, followed by fluorouracil 1,000 mg/m² as a continuous infusion from day 1 to day 4. This regimen is administered every three weeks for three cycles. Following chemotherapy, patients should receive chemoradiotherapy.

Premedication in breast, non-small cell lung, ovarian and head and neck cancers.

Premedication in prostate cancer.

For prostate cancer, given the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg 12 hours, three hours and one hour before the docetaxel infusion.

Dosage adjustments during treatment.

DBL Docetaxel Concentrated Injection should be administered when the neutrophil count is greater than or equal to 1.5 x 10⁹ cells/L.

In patients treated at 75 mg/m².

Patients who experienced either febrile neutropenia, neutrophils < 0.5 x 10⁹ cells/L for more than one week, severe or cumulative cutaneous reactions or severe neurosensory signs and/or symptoms during docetaxel therapy should have the dosage of docetaxel reduced from 75 mg/m² to 55 mg/m² (or to 60 mg/m² for adjuvant therapy for breast cancer). If the patient continues to experience these reactions at 55 mg/m² (or at 60 mg/m²), the treatment should be discontinued.

In patients treated at 100 mg/m².

Patients who experienced either febrile neutropenia, neutrophils < 0.5 x 10⁹ cells/L for more than one week, severe or cumulative cutaneous reactions or severe neurosensory signs and/or symptoms during docetaxel therapy should have the dosage of docetaxel reduced from 100 mg/m² to 75 mg/m². If the patient continues to experience these reactions at 75 mg/m², either the dosage should be decreased from 75 mg/m² to 55 mg/m² or the treatment should be discontinued.

Patients treated with docetaxel in combination with capecitabine.

For capecitabine dose modifications when combined with docetaxel, see capecitabine product information.
For patients developing the first appearance of a grade 2 toxicity which persists at the time of the next docetaxel/ capecitabine treatment, delay treatment until resolved to grade 0 to 1, and resume at 100% of the original dose.
For patients developing the second appearance of a grade 2 toxicity, or the first appearance of a grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to grade 0 to 1, then resume treatment with docetaxel 55 mg/m².
For any subsequent appearances of toxicities, or any grade 4 toxicities, discontinue the docetaxel dose.

Patients treated with docetaxel in combination with trastuzumab.

Patients treated with docetaxel in combination with doxorubicin and cyclophosphamide.

In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up (see Section 4.8 Adverse Effects (Undesirable Effects)).
Primary G-CSF prophylaxis should be considered in patients who receive TAC adjuvant therapy for breast cancer. Patients who receive adjuvant therapy for breast cancer and who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience febrile neutropenia and/or neutropenic infection should remain on G-CSF and have their docetaxel dose reduced to 60 mg/m². If G-CSF is not used, the docetaxel dose should be reduced from 75 to 60 mg/m². Patients who experience grade 3 or 4 stomatitis should have their dose decreased to 60 mg/m².

Patients treated with docetaxel in AC-TH or TCH.

Patients who received AC-TH or TCH adjuvant therapy for operable breast cancer whose tumours overexpress HER2 and who experience an episode of febrile neutropenia or infection should receive prophylactic G-CSF in all subsequent cycles. For a second episode of febrile neutropenia or infection, patients should continue prophylactic G-CSF, and docetaxel will be reduced from 100 mg/m² to 75 mg/m² (in the AC-TH regimen); docetaxel will be reduced from 75 mg/m² to 60 mg/m² (in the TCH regimen).
However, in clinical practice neutropenia could occur in cycle 1. Thus, G-CSF should be used in consideration of the neutropenic risk of the patient and current recommendations. Depending on the treatment regimen, patients who experience grade 3 or 4 stomatitis should have their dose decreased from 100 mg/m² to 75 mg/m² (in the AC-TH regimen) or from 75 mg/m² to 60 mg/m² in the TCH regimen).

Patients treated with docetaxel in combination with cisplatin and fluorouracil in head and neck cancer.

Patients treated with docetaxel in combination with cisplatin and fluorouracil must receive antiemetics and appropriate hydration according to current institutional guidelines. G-CSF should be administered to mitigate the risk of complicated neutropenia.
If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m². If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m².
In case of grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m². Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level > 1,500 cells/mm³ and platelets recover to a level > 100,000 cells/m³. Discontinue treatment if these toxicities persist.
For cisplatin and fluorouracil dosage and administration, see the relevant product information.
Recommended dose modifications for toxicities in patients treated with docetaxel in combination with cisplatin and fluorouracil are shown in Table 1.

Use in renal impairment.

No information available.

Use in hepatic impairment.

Patients with hepatic impairment in patients treated at 75 mg/m².

For those patients with increased serum bilirubin and/or values > 3.5 times the upper limit of normal (ULN) for ALT and AST and > six times the ULN for alkaline phosphatase, no dose reduction can be recommended and docetaxel should not be used unless strictly indicated.

In patients treated at 100 mg/m².

Based on the pharmacokinetic data, in patients who have both elevations of transaminase values (ALT and/or AST greater than 1.5 times the ULN) and increases in alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m² (see Section 5.2 Pharmacokinetic Properties). For those patients with increased serum bilirubin and/or values > 3.5 times the ULN for ALT and AST and > six times the ULN for alkaline phosphatase, no dose reduction can be recommended and docetaxel should not be used unless strictly indicated.
For capecitabine dosage reduction when combined with docetaxel, see capecitabine product information.

Dialysis.

No information available.

Concomitant disease.

No information available.

Maximum tolerated daily dose and the maximum dose for an entire course of therapy.

The maximum daily dose is 100 mg/m². The maximum dose per course is not specified.

Monitoring advice.

Frequent monitoring of complete blood counts should be conducted on all patients during treatment with docetaxel.

Use in children.

The safety and effectiveness of docetaxel in children have not been established.

Use in the elderly.

Based on the population pharmacokinetics, there are no special instructions for use in the elderly.
For capecitabine dosage reduction when combined with docetaxel see capecitabine product information.

Instruction for use/ handling.

As with all parenteral products, DBL Docetaxel Concentrated Injection should be visually inspected prior to use. Solutions containing a precipitate should be discarded.
Contact of DBL Docetaxel Concentrated Injection with plasticised PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticiser DEHP (di-2-ethylhexyl phthalate), which may be leached from PVC infusion bags or sets, the final DBL Docetaxel Concentrated Injection, Concentrated Injection dilution for infusion should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

Preparation and storage of the infusion solution.

Based on the required dose for the patient expressed in mg, aseptically withdraw the corresponding volume from the appropriate number of vials using a graduated syringe fitted with a needle. For example, a dose of docetaxel 140 mg would require 14 mL DBL Docetaxel Concentrated Injection solution.
Inject the required volume into a 250 mL infusion bag or bottle containing either sodium chloride 0.9% solution or glucose 5% solution. If a dose greater than docetaxel 200 mg is required, use a larger volume of the infusion vehicle so that a concentration of docetaxel 0.74 mg/mL is not exceeded. Mix the infusion bag or glass bottle manually using a rocking motion.
DBL Docetaxel Concentrated Injection solution for infusion should be aseptically administered intravenously as a one hour infusion under room temperature and normal lighting conditions.
The solution for infusion is stable at room temperature (25°C) for up to four hours. However, to reduce microbiological hazards and the risk of crystallisation of docetaxel from diluted solutions, it is recommended that dilution should be effected immediately prior to use and infusion commenced as soon as practicable after preparation of the solution for infusion. If storage is necessary, hold at 2-8°C for not more than 24 hours.
Any residue after infusion should be discarded. Any solutions which are discoloured, hazy or contain visible particulate matter should not be used.

Disposal.

All materials that have been utilised for dilution and administration should be disposed of according to standard procedures.

Recommendations for safe handling.

DBL Docetaxel Concentrated Injection is an antineoplastic agent and, as with other potentially toxic compounds, caution should be exercised when handling it and preparing docetaxel solutions. The use of gloves is recommended.
If DBL Docetaxel Concentrated Injection or docetaxel infusion solution comes into contact with the skin, wash immediately and thoroughly with soap and water. If DBL Docetaxel Concentrated Injection or docetaxel infusion solution comes into contact with mucous membranes, wash immediately and thoroughly with water.
Each presentation must be diluted prior to intravenous administration. Use in one patient on one occasion only.

4.3 Contraindications

History of severe hypersensitivity reactions to docetaxel or any of the excipients.
Baseline neutrophil count of < 1.5 x 10⁹ cells/L.
Severe liver impairment.
Pregnant or breastfeeding women.
Contraindications that apply for other drugs also apply when these drugs are combined with DBL Docetaxel Concentrated Injection.

4.4 Special Warnings and Precautions for Use

The use of DBL Docetaxel Concentrated Injection should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a qualified oncologist.

Premedication.

Patients should be pre-treated prior to each DBL Docetaxel Concentrated Injection administration. A premedication consisting of an oral corticosteroid, e.g. dexamethasone 16 mg/day (e.g. 8 mg twice daily) for three days starting one day prior to DBL Docetaxel Concentrated Injection administration, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions (see Fluid retention and Hypersensitivity reactions, below; also see Section 4.2 Dose and Method of Administration).
For prostate cancer, the premedication is oral dexamethasone 8 mg, 12 hours, three hours and one hour before the docetaxel infusion.

Haematology.

Bone marrow suppression and other haematological effects of docetaxel include neutropenia, the most frequent adverse effect of docetaxel (see Section 4.8 Adverse Effects (Undesirable Effects), Clinical studies). Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pretreated patients. Frequent monitoring of complete blood counts should be conducted in all patients receiving docetaxel. Patients should be retreated with docetaxel only when neutrophils recover to a level greater than or equal to 1.5 cells x 10⁹/L.
DBL Docetaxel Concentrated Injection should not be administered to patients with baseline neutrophil counts of < 1.5 x 10⁹ cells/L. Frequent monitoring of complete blood counts should be conducted on all patients during treatment with docetaxel. Patients should not be retreated with DBL Docetaxel Concentrated Injection until neutrophils recover to a level greater than or equal to 1.5 x 10⁹ cells/L (see Section 4.2 Dose and Method of Administration).
In the case of severe neutropenia (< 0.5 x 10⁹ cells/L for seven days or more) during a course of DBL Docetaxel Concentrated Injection therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures is recommended. Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.
Patients treated with TPF and TAC should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients who continue to experience this reaction should remain on G-CSF and have their DBL Docetaxel Concentrated Injection dose reduced (see Section 4.2 Dose and Method of Administration, Dosage adjustments during treatment). Patients receiving TPF and TAC should be closely monitored (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
In the treatment of adjuvant breast cancer, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up (see Section 4.8 Adverse Effects (Undesirable Effects)).

Gastrointestinal reactions.

Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Haematology; Section 4.8 Adverse Effects (Undesirable Effects)). Although majority of cases occurred during the first or second cycle of docetaxel containing regimen, enterocolitis could develop at any time, and could lead to death as early as on the first day of onset. Patients should be closely monitored for early manifestations of serious gastrointestinal toxicity.

Hypersensitivity reactions.

Patients should be observed closely for hypersensitivity reactions, especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes of, during or immediately following the cessation of the infusion of DBL Docetaxel Concentrated Injection, thus facilities for the treatment of hypotension and bronchospasm should be available. Frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and drug fever or chills. If hypersensitivity reactions occur, minor symptoms such as flushing or localised cutaneous reactions do not require interruption of therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised rash/ erythema, require immediate discontinuation of DBL Docetaxel Concentrated Injection and aggressive therapy. Severe symptoms are usually resolved after discontinuing the infusion and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be rechallenged with DBL Docetaxel Concentrated Injection. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to docetaxel, including more severe hypersensitivity reaction. These patients should be closely monitored during initiation of docetaxel therapy.

Cutaneous reactions.

Reversible cutaneous reactions were generally mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on feet, hands (including severe hand and foot syndrome), but also arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the docetaxel infusion. Less frequently, severe symptoms, e.g. eruptions followed by desquamation which rarely led to interruption or discontinuation of docetaxel treatment were reported. Nail disorders were characterised by hypopigmentation or hyperpigmentation, pain and onycholysis.
Very rare cases of cutaneous lupus erythematosus and bullous eruptions, e.g. erythema multiforme, scleroderma-like changes and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and acute generalized exanthematous pustulosis (AGEP) have been reported with docetaxel treatment. Patients should be informed about the signs and symptoms of serious skin manifestations and closely monitored. If signs and symptoms suggestive of these reactions appear, discontinuation of docetaxel should be considered. In some cases, multiple factors such as concomitant infections, concomitant medications and underlying disease may have contributed to the development of these effects.

Ear and labyrinth disorders.

Rare cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.

Eye disorders.

Cystoid macular oedema (CMO) has been reported in patients treated with docetaxel. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case cystoid macular oedema is diagnosed, docetaxel treatment should be discontinued and appropriate treatment initiated.

Fluid retention.

A premedication consisting of an oral corticosteroid, e.g. dexamethasone 16 mg/day (e.g. 8 mg twice daily) for three days starting one day prior to docetaxel administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions (see Section 4.2 Dose and Method of Administration).
The peripheral oedema usually starts at the lower extremities and may become generalized with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity; however, it has been reported in some patients during early courses of therapy. The median cumulative dose to onset for treatment with 75 mg/m² is 524 mg/m² and treatment at 100 mg/m² is 509 mg/m² (without premedication) and 797 mg/m² (with premedication). Fluid retention is slowly reversible after docetaxel treatment is stopped. In patients treated by docetaxel as single agent at 100 mg/m², the median cumulative dose to treatment discontinuation was more than 1,000 mg/m² and the median time to fluid retention reversibility was 16.4 weeks (range 0 to 42 weeks).
Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored more closely.
Patients developing peripheral oedema may be treated with standard measures.

Respiratory disorders.

Acute respiratory distress syndrome, interstitial pneumonia/pneumonitis, interstitial lung disease, pulmonary fibrosis and respiratory failure have been reported and may be associated with fatal outcome. Cases of radiation pneumonitis have been reported in patients receiving concomitant radiotherapy. If new or worsening pulmonary symptoms develop, patients should be closely monitored, promptly investigated, and appropriately treated. Interruption of docetaxel therapy is recommended until diagnosis is available. Early use of supportive care measures may help improve the condition. The benefit of resuming docetaxel treatment must be carefully evaluated.

Nervous system.

The development of severe neurosensory signs and/or symptoms have been observed in patients and require a reduction of dose (see Section 4.2 Dose and Method of Administration).

Cardiac toxicity.

Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin and epirubicin) containing chemotherapy. This may be moderate to severe and has been associated with death.
When patients are candidates for treatment with docetaxel in combination with trastuzumab, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction.

Tumour lysis syndrome.

Tumour lysis syndrome has been reported with docetaxel after the first or the second cycle (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients at risk of tumour lysis syndrome (e.g. with renal impairment, hyperuricemia, bulky tumour, rapid progression) should be closely monitored. Correction of dehydration and treatment of high uric acid levels are recommended prior to initiation of treatment.

CYP3A4 inhibitors.

The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Additional cautions for use in adjuvant treatment of breast cancer.

Complicated neutropenia.

For patients who experience complicated neutropenia (prolonged neutropenia, febrile neutropenia or infection), G-CSF and dose reduction should be considered (see Section 4.2).

Gastrointestinal reactions.

Early abdominal pain and tenderness, fever, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure (CHF).

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow up period.
In patients treated with the TAC regimen for node positive breast cancer, the risk of CHF has been shown to be higher during the first year after treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

Leukaemia.

In the adjuvant treatment of breast cancer, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow up.

Alcohol content.

DBL Docetaxel Concentrated Injection contains ethanol.
The alcohol content is harmful for those suffering from alcoholism.
The alcohol content is to be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.
Consideration should be given to possible effects on the central nervous system.
Co-administration with medicines containing e.g. propylene glycol or ethanol may lead to accumulation of ethanol and induce adverse effects, particularly in young children with low or immature metabolic capacity.

Use in hepatic impairment.

Liver function tests (LFTs) should be measured at baseline and before each cycle. In patients treated with docetaxel at 100 mg/m² who have both elevations of serum transaminase values (ALT and/or AST) > 1.5 times the upper limit of normal and increases in alkaline phosphatase > 2.5 times the upper limit of normal, there is a greater risk of developing severe adverse effects such as toxic deaths including sepsis, gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. The recommended dose of docetaxel in patients with elevated LFTs is 75 mg/m² (see Section 4.2 Dose and Method of Administration).
For patients with increased serum bilirubin and/or values > 3.5 times the upper limit of normal for ALT and AST, and > 6 times the upper limit of normal for alkaline phosphatase, no dose reduction can be recommended and docetaxel should not be used unless strictly indicated.
No data are available in patients with hepatic impairment treated by docetaxel in combination therapy.

Use in renal impairment.

There are no data available in patients with severely impaired renal function treated with docetaxel.

Use in the elderly.

An analysis of safety data in patients equal to or greater than 60 years of age treated with docetaxel in combination with capecitabine showed an increase in the incidence of treatment related grade 3 or 4 adverse effects, treatment-related serious adverse effects and early withdrawals from treatment due to adverse effects compared to patients less than 60 years of age.

Use in castration-resistant prostate cancer.

Of the 333 patients treated with docetaxel every three weeks for metastatic castration-resistant prostate cancer in the prostate cancer study, 209 patients were 65 years of age or greater and 68 patients were older than 75 years. Differences in efficacy were not identified between elderly patients and younger patients. In patients treated with docetaxel every three weeks, the incidence of anaemia, infection, nail changes, anorexia, weight loss occurred at rates ≥ 10% higher in patients who were 65 years of age or greater compared to younger patients.

Use in adjuvant treatment of breast cancer.

There are no data available in patients > 70 years of age on docetaxel use in combination with doxorubicin and cyclophosphamide.
The proportion of elderly patients was 5.5% and 6.6% in the AC-TH and TCH regimens, respectively, and is too limited to allow for conclusions regarding the adverse events occurring by age (< 65 years vs. greater than or equal to 65 years).
Of the 174 and 251 patients who received the induction treatment with docetaxel in combination with cisplatin and fluorouracil (TPF) for SCCHN in the TAX 323 and TAX 324 studies, only 18 (10%) and 32 (13%), respectively, of the patients were 65 years of age or older. The number of elderly patients who received this regimen was not sufficient to determine whether geriatric patients responded differently from younger patients. Elderly patients treated with TPF should be closely monitored.

Paediatric use.

The safety and effectiveness of docetaxel in children have not been established.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

There have been no formal clinical studies to evaluate the drug interactions of docetaxel.
In vitro studies suggest that isoenzymes of the cytochrome P450-3A subfamily appear to be involved in the hepatic metabolism of docetaxel in humans. In vitro, the biotransformation of docetaxel was inhibited by ciclosporin, terfenadine, ketoconazole, erythromycin and troleandomycin and to a lesser extent by doxorubicin, vinorelbine, vinblastine and nifedipine, increased by dexamethasone, phenobarbitone and clofibrate and unaffected by cimetidine, ranitidine, omeprazole, diazepam, imipramine, paracetamol, caffeine, tolbutamide and quinidine. Strong P450-3A inhibitors may affect docetaxel metabolism in vivo, necessitating caution in co-administration regimens.
The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their co-administration.
In a pharmacokinetic study with 7 patients, the co-administration of docetaxel with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in docetaxel clearance by 49%. In case of combination with CYP3A4 inhibitors, the occurrence of docetaxel adverse reactions may increase, as a result of reduced metabolism. The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided. If the concomitant use of a strong CYP3A4 inhibitor cannot be avoided, a close clinical surveillance is warranted and a dose-adjustment of docetaxel may be suitable during concomitant treatment with the strong CYP3A4 inhibitor.
In vitro, plasma protein binding was more than 95%, with the important proteins being albumin, alpha₁-acid glycoprotein and lipoproteins. The in vitro plasma protein binding of docetaxel was not affected by dexamethasone, erythromycin, salicylate, sulfamethoxazole, diphenhydramine, propranolol, propafenone, phenytoin and sodium valproate. The binding of digitoxin was not affected by docetaxel.
In vivo investigations show that caution should be exercised when administering ketoconazole to patients as concomitant therapy since there is a potential for a significant interaction.
Docetaxel should be administered with caution in patients concomitantly receiving protease inhibitors (e.g. ritonavir) which are inhibitors and substrates of cytochrome P450-3A.
The amount of alcohol in this medicinal product may alter the effects of other medicinal products.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in mice have shown that intravenous doses of 144 mg/m² or 30 mg/m²/day for five days are associated with testicular atrophy, mineralisation and degeneration of tubular germinal epithelium, Leydig cell hyperplasia and epididymal hypospermia and follicular atresia in the ovaries. Studies in rats have shown that intravenous doses of 120 mg/m² are associated with testicular atrophy, germ cell atrophy, Leydig cell hyperplasia and mineralisation. The rodent studies suggest that docetaxel may impair fertility. Studies in rats have also shown that intravenous doses of 0.9 mg/m²/day to both sexes are associated with reduced litter averages for corpora lutea, implantations and live foetuses, and increased litter averages for early and total resorptions. Larger doses to both sexes (males 1.8 mg/m²/day, females 1.35 mg/m²/day) are additionally associated with increased time to mating, increased number of dams with total resorption, and reduced male fetal bodyweight.
An adverse effect on male or female fertility cannot be excluded. Therefore, men being treated with docetaxel are advised to seek advice on conservation of sperm prior to treatment, and all patients intending to have a child after treatment are advised to consider individual genetic counselling.
(Category D)
Docetaxel may cause fetal harm when administered to a pregnant woman. Therefore, docetaxel must not be used during pregnancy.
Fetal radioactivity has been detected following intravenous administration of radiolabelled docetaxel to pregnant rats. Docetaxel has been shown to be embryotoxic and fetotoxic in rats and rabbits. At intravenous doses of 0.9 mg/m², docetaxel caused fewer corpora lutea, fewer implantations, increased resorptions and embryofoetal deaths in rats. No evidence of teratogenic effects was found when docetaxel was administered intravenously at doses up to 1.8 mg/m² or 1.2 mg/m² in rats or rabbits, respectively, but reduced fetal weight and delayed ossification were observed.
Offspring from rats receiving docetaxel 1.5 mg/m²/day intravenously from late gestation until weaning showed signs of delayed development. No studies have been performed in pregnant women.
If docetaxel is used during pregnancy, or if the patient becomes pregnant while receiving this drug, she should be apprised of the potential hazard. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with this drug and to inform the treating physician immediately should this occur.

Contraception in males and females.

Based on reproductive toxicity and genetic toxicity findings, women of childbearing potential should be advised to use effective contraception during treatment with docetaxel and for at least 6 months after the last dose.
Based on genetic toxicity findings, male patients with female partners of childbearing potential should be advised to use effective contraception during treatment with docetaxel and for at least 3 months after the last dose.
Radioactivity has been detected in milk following intravenous administration of radiolabelled docetaxel to lactating rats. Offspring from rats receiving docetaxel 1.5 mg/m²/day intravenously during late gestation and lactation showed signs of delayed development. It is not known whether docetaxel is excreted in human milk. It is recommended to advise women not to breastfeed during treatment with docetaxel and for 1 week after the last dose.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effect on the ability to drive and use machines have been performed. Patients should refrain from driving or using machines until they know that the docetaxel does not negatively affect these abilities.
The amount of ethanol in docetaxel may impair the ability to drive or use machines. The alcohol content in a maximum recommended dose of 200 mg (based on 100 mg/m², body surface area 2.0 m²) contains approximately 1.8 gram of absolute ethanol.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

Monotherapy.

Breast, non-small cell lung and ovarian cancer. The adverse effects considered to be possibly or probably related to starting the administration of docetaxel have been obtained from 75 patients who received a dose of 75 mg/m² without the recommended premedication and from 2,106 (2,045 with normal* and 61 with elevated* LFTs at baseline) patients who received an initially planned dose of 100 mg/m² over a one hour infusion every three weeks independently of the premedication. The patients were enrolled in 40 phase II and III studies conducted in Europe and North America (991 with breast carcinoma, 668 with non-small cell lung carcinoma and 447 with various tumour types).
The safety profile is generally similar between patients receiving docetaxel for the treatment of breast, non-small cell lung or ovarian carcinoma. Table 2 lists the adverse effect data.

35 toxic deaths (1.7%) were reported in the 2,045 patients with normal baseline liver function tests treated with docetaxel as monotherapy at the initially planned dose of 100 mg/m². Septic deaths (neutropenic infections, pneumonia or sepsis) accounted for 80% of the toxic deaths. The incidence of toxic deaths was higher (9.8%) in patients with elevated baseline LFTs.
Hypersensitivity reactions generally occurred within a few minutes of the start of infusion and were generally mild to moderate. Frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and drug fever or chills (see Section 4.4 Special Warnings and Precautions for Use).

Haematological.

Bone marrow suppression and other haematological adverse reactions to docetaxel include the following:
Neutropenia (in patients who did not receive G-CSF), the most frequent adverse effect, was reversible and not cumulative. The median day to nadir was seven days and the median duration of severe neutropenia was seven days.
Febrile neutropenia and severe infections associated with neutrophil counts < 0.5 x 10⁹/L, infectious episodes (severe including sepsis pneumonia, fatal in 1.7%), occurred. Thrombocytopenia, bleeding episodes (rarely associated with severe thrombocytopenia) and anaemia (severe) were also reported.
Disseminated intravascular coagulation (DIC), often in association with sepsis, or multiorgan failure, has been reported.

Neurological.

Mild to moderate neurosensory signs and/or symptoms occurred in 50% of the patients. Severe neurosensory symptoms (paraesthesia, dysaesthesia, pain including burning) were observed in 4.1% of metastatic breast cancer patients and resulted in treatment discontinuation in 2%. Neuro-motor events (13.8% with 4% severe) were mainly characterised by weakness. When these symptoms occur, dosage must be adjusted. If symptoms persist, treatment should be discontinued. Patients who experienced neurotoxicity in clinical trials and for whom follow-up information on the complete resolution of the event were available had spontaneous reversal of symptoms with a median of 81 days from onset (range 0 to 741 days).
Rare cases of convulsion or transient loss of consciousness have been observed with docetaxel administration. These reactions sometimes appear during the infusion of the drug.

Hepatic.

In patients treated at 100 mg/m² as a single agent, increase in serum levels of AST, ALT, bilirubin and alkaline phosphatase greater than 2.5 the ULN were observed in less than 5% of patients. Very rare cases of hepatitis have been reported.

Combination therapy.

Breast cancer. Metastatic breast cancer. Combination with capecitabine. The adverse effect profile is consistent with the known toxicities of monotherapy treatments.
The most frequent treatment related adverse effects (greater than or equal to 5%) reported in the phase III clinical trial for docetaxel in combination with capecitabine in patients with locally advanced and/or metastatic breast cancer (n = 251) are shown in Table 3.
The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (20%) in the monotherapy arm discontinued from the trial because of adverse effects. The percentages of patients requiring dose reductions due to adverse effects were 65% in the combination arm and 36% in the monotherapy arm.

Frequent grade 3 and 4 laboratory abnormalities are shown in Table 4.

Rare or uncommon adverse effects, as described for capecitabine monotherapy, can be expected for combination therapy as well. See capecitabine product information for adverse effects which are at least remotely related to capecitabine occurring in < 5% of patients treated with capecitabine in combination with docetaxel.
Combination with trastuzumab (HER2+). See Table 5.

There was an increased incidence of SAEs (40% vs. 31%) and grade 4 AEs (34% vs. 23%) in the combination arm compared to docetaxel monotherapy.

Cardiac toxicity.

The incidence of symptomatic congestive heart failure in the study of docetaxel plus trastuzumab versus docetaxel alone is shown in Table 6.

In this study, all patients had a baseline cardiac ejection fraction of greater than 50%. In the docetaxel plus trastuzumab arm, 64% had received a prior anthracycline as adjuvant therapy, compared with 55% in the docetaxel alone arm.

Haematological toxicity.

Grade 3/4 neutropenia was reported in 32% of the patients given docetaxel plus trastuzumab.

Adjuvant treatment of breast cancer.

Combination with doxorubicin and cyclophosphamide. Table 7 presents clinically important treatment emergent adverse events (TEAEs) observed in 744 patients who were treated with docetaxel 75 mg/m² every three weeks in combination with doxorubicin and cyclophosphamide and 736 patients treated with the comparator study drugs.

Of the 744 patients treated with TAC (docetaxel, doxorubicin and cyclophosphamide), 33.1% experienced severe TEAEs. Dose reductions due to haematological toxicity occurred in 1% of cycles in TAC arm. 6% of patients treated with TAC discontinued treatment due to adverse events, fever in the absence of infection and allergy being the most common reasons for withdrawal. Two patients died within 30 days of their last study treatment; 1 death was considered to be related to study drug.

Fever and infection.

Fever in the absence of infection was seen in patients and infection was seen in patients. There were no septic deaths.

Gastrointestinal events.

In addition to gastrointestinal events reflected in Table 7, four patients were reported to have colitis/ enteritis/ large intestine perforation in the TAC arm. Two of these patients required treatment discontinuation; no deaths due to these events occurred during the treatment period.

Acute myeloid leukaemia/ myelodysplastic syndrome.

At a median follow-up time of 83 months, AML occurred in three of 744 (0.4%) patients who received docetaxel, doxorubicin and cyclophosphamide and in one of 736 (0.1%) patients who receive fluorouracil, doxorubicin and cyclophosphamide.

Cardiovascular events.

The following cardiovascular events were reported: dysrhythmias, all grades (3.9%), hypotension, all grades (1.5%) and CHF (2.3% at 70 months median follow-up). One patient died due to heart failure.

Other persistent reactions.

The following events were observed to be ongoing at the median follow-up time of 55 months: alopecia, amenorrhoea, neurosensory and peripheral oedema. Among the adverse events that persisted into the follow-up period in > 1% of patients, the majority of events resolved; however, amenorrhoea, and lymphoedema remained ongoing in TAC patients.
Combination with doxorubicin, cyclophosphamide and trastuzumab and with carboplatin and trastuzumab (HER2+). See Table 8.

The 3-year cumulative incidence of all symptomatic cardiac events was 2.36% and 1.16% in the AC-TH and TCH arms, respectively (versus 0.52% in the AC-T control arm, see Section 5.1 Pharmacodynamic Properties). The 3-year cumulative incidence of CHF events (grade 3 or 4) was 1.9% and 0.4% in the AC-TH and TCH arms, respectively (versus 0.3% in the AC-T control arm).
Combination with cyclophosphamide (TC). Whilst overall the toxicity profiles were similar, there were some differences between TC and AC (doxorubicin and cyclophosphamide). AC was associated with more nausea and vomiting (all grades as well as grades 3 and 4), but TC had more low-grade oedema, myalgia, and arthralgia secondary to the use of docetaxel. The exception was cardiac toxicity. In the AC arm one patient died of congestive heart failure and there were four deaths due to myocardial infarction. At the 7-year follow up another death in the AC arm was attributed to congestive heart failure. In the TC arm there were no deaths attributed to congestive heart failure and two deaths from myocardial infarction.
See Table 9.

Prostate cancer.

Combination with prednisone (or prednisolone).

The adverse effect profile is consistent with the known safety profile of docetaxel. Table 10 provides the percentage of subjects with clinically important TEAs and haematological toxicities related to study treatment reported in the phase III clinical trial for docetaxel 75 mg/m² q3w (every three weeks) and mitozantrone q3w in combination with prednisone (or prednisolone).

Head and neck cancer.

Combination with cisplatin and fluorouracil.

Table 11 summarises the safety data obtained in 174 (TAX 323) and 251 patients (TAX 324) with locally advanced SCCHN who were treated with docetaxel 75 mg/m² in combination with cisplatin and fluorouracil.

Postmarketing adverse effects.

The following information relates to serious events observed following the marketing of docetaxel. Voluntary reports of serious adverse events that have been received since market introduction (without causal relationship) that are not listed previously are cited below. Frequency estimates are as follows. Common: greater than or equal to 1 to 10%; uncommon: 0.1 to 1%; rare: 0.01 to 0.1%; very rare: < 0.01%.

Body as a whole.

Uncommon: chest pain, diffuse pain.
Rare: abdominal pain.
Very rare: radiation recall phenomenon.

Hypersensitivity.

Rare: cases of anaphylactic shock have been reported.
Very rare: these cases resulted in a fatal outcome in patients who received premedication.
Hypersensitivity reactions such as bronchospasm and generalized rash have been reported.
Hypersensitivity reactions have been reported with docetaxel in patients who previously experienced hypersensitivity reactions to paclitaxel.

Cutaneous.

Very rare: cases of cutaneous lupus erythematous and bullous eruptions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and scleroderma-like changes have been reported. Multiple factors such as concomitant infections, concomitant medications and underlying disease may have contributed to the development of these effects. Cases of permanent alopecia have been reported.
Severe nail disorders characterised by hypo- or hyperpigmentation, and infrequently onycholysis and pain.
Acute generalized exanthematous pustulosis has been reported.

Fluid retention.

Rare: dehydration and pulmonary oedema have been reported.

Gastrointestinal.

Rare: constipation, oesophagitis and taste perversion, ileus and intestinal obstruction, gastrointestinal perforation, neutropenic enterocolitis^a, colitis^a, including ischaemic colitis^a, gastrointestinal haemorrhage, dehydration as a consequence of gastrointestinal events.
Very rare: duodenal ulcer.
^a Reported with a fatal outcome.

Neurological.

Rare: confusion, seizures, transient loss of consciousness. These reactions sometimes occur during infusion of the drug.

Cardiovascular.

Common: hypertension, hypotension.
Uncommon: cardiac arrhythmia^b, congestive heart failure.
Rare: atrial fibrillation, syncope, tachycardia^b.
Very rare: deep vein thrombosis, myocardial infarction, ECG abnormalities, thrombophlebitis, pulmonary embolism.
Vein disorder, venous thromboembolism and haemorrhage have been reported.
^b In post-marketing, ventricular arrhythmia including ventricular tachycardia has been reported in patients treated with docetaxel in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide, and may be associated with fatal outcome.

Hepatic.

Very rare: hepatitis, sometimes fatal, primarily in patients with pre-existing liver disorders, has been reported.

Ear and labyrinth disorders.

Rare: cases of ototoxicity, hearing disorders and/or hearing loss have been reported, including cases associated with other ototoxic drugs.
Hypoacusis has been recorded.

Eye disorders.

Rare: cases of lacrimation with or without conjunctivitis have been reported and very rare cases of lacrimal duct obstruction resulting in excessive tearing have been reported primarily in patients receiving other antitumour agents concomitantly.
Cases of transient visual disturbances (flashes, flashing lights, scotomata) typically occurring during drug infusion and in association with hypersensitivity have been reported. These were reversible upon discontinuation of the infusion.
Cases of cystoid macular oedema (CMO) have been reported in patients treated with docetaxel as well as with other taxanes.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnoea.
Rare: acute respiratory distress syndrome, interstitial pneumonia/ pneumonitis, interstitial lung disease, acute pulmonary oedema, pulmonary fibrosis, and radiation recall phenomena have rarely been reported. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant therapy.
Respiratory failure has been reported.

Haematological and lymphatic disorders.

Very rare: cases of acute myeloid leukaemia and myelodysplastic syndrome have been reported in association with docetaxel when used in combination with other chemotherapy agents and/or radiotherapy.
Disseminated intravascular coagulation (DIC), often in association with sepsis or multiorgan failure, has been reported.

Urogenital.

Rare: renal insufficiency and renal failure associated with concomitant nephrotoxic drugs have been reported.

Musculoskeletal and connective tissue disorders.

Myositis has been reported.

Other.

Common: generalised or localised pain including chest pain without cardiac or respiratory involvement.

Metabolism and nutrition disorders.

Tumour lysis syndrome has been reported. Cases of electrolyte imbalance have been reported. Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia. Hypokalaemia, hypomagnesaemia and hypocalcaemia were observed, usually in association with gastrointestinal disorders and in particular diarrhoea.

General disorders and administration site conditions.

Fluid retention (pleural effusion, pericardial effusion, ascites), injection site recall reaction (recurrence of skin reaction at a site of previous extravasation following administration of docetaxel at a different site) has been observed at the site of previous extravasation.

Investigations.

Liver function test abnormal, weight decreased, blood bilirubin increased, blood alkaline phosphatase increased, AST increased, ALT increased.

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

Symptoms.

There were two reports of overdose. One patient received docetaxel 150 mg/m² and the other received docetaxel 200 mg/m² as a one hour infusion. They both recovered after experiencing severe neutropenia, mild asthenia, cutaneous reactions and mild paraesthesia.

Treatment.

In case of overdosage, the patient should be kept in a specialised unit and vital functions closely monitored. Exacerbation of adverse events may be expected. There is no known antidote for docetaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Docetaxel has been shown in vitro to disrupt the microtubular network in cells which is essential for vital mitotic and interphase cellular functions.

Class.

Docetaxel is an antineoplastic agent which acts by promoting the assembly of tubulin into stable microtubules and inhibits their disassembly which leads to a marked decrease of free tubulin. The binding of docetaxel to microtubules does not alter the number of protofilaments.

Clinical trials.

Breast cancer.

Metastatic breast cancer. Monotherapy. Eight phase II studies were conducted in patients with locally advanced or metastatic breast carcinoma. A total of 172 patients had received no prior chemotherapy (previously untreated) and 111 patients had received prior chemotherapy (previously treated) which included 83 patients who had progressive disease during anthracycline therapy (anthracycline resistant). In these clinical trials, docetaxel was administered at a dose of 75 mg/m² in 55 previously untreated patients and at a dose of 100 mg/m² in 117 previously untreated and 111 previously treated patients. In these trials, docetaxel was administered as a one-hour infusion every three weeks.

Patients treated at 75 mg/m².

In the intent to treat analysis on previously untreated patients, the overall response rate was 47% with 9% complete responses. The median duration of response was 34 weeks and the time to progression was 22 weeks.
There was a high response rate in patients with visceral metastases (48.6% in 35 untreated patients).
In patients with two or less organs involved, the response rate was 58.6% and in patients with three or more organs involved, it was 29.4%.
A significant response rate was seen in patients with liver metastases (45% in untreated patients). The same activity is maintained in untreated patients with soft tissue disease (55.5%).

Patients treated at 100 mg/m². Phase II trials.

In the intent to treat analysis on previously untreated patients, the overall response rate was 56% with 9.4% complete responses. The overall response rate was 48.6% with 3.6% complete responses in the previously treated population including 48.2% overall response rate with 3.6% complete response in the anthracycline resistant patients. The median duration of response was 30 weeks in the previously untreated population, 28 weeks in the previously treated population and 27 weeks in the anthracycline resistant patients. The time to treatment failure was 21 weeks in the previously untreated population, 19 weeks in the previously treated population and 19 weeks in the anthracycline resistant patients.
The 100 mg/m² dose is associated with higher toxicity.
There was a high response rate in patients with visceral metastases (53.8% in 78 untreated patients, 55.1% in 69 pre-treated patients and 53.1% in the subgroup of 49 anthracycline resistant patients).
In patients with three or more organs involved, the response rate was 54.3% in previously untreated patients, 55.8% in previously treated patients and 50% in the subgroup of anthracycline resistant patients.
A significant response rate was seen in patients with liver metastases (59.5% in untreated patients, 47.2% in previously treated patients and 40% in the subgroup of anthracycline resistant patients). The same activity is maintained in patients with visceral involvement (70.4% in previously untreated patients, 63.6% in previously treated patients and 63.2% in the subgroup of anthracycline resistant patients).

Patients treated at 100 mg/m². Phase III trials.

Two randomised phase III comparative studies, involving a total of 326 alkylating agent failure and 392 anthracycline failure metastatic breast cancer patients, have been performed with docetaxel 100 mg/m² administered every three weeks for seven and ten cycles, respectively.
In alkylating agent failure patients, there were no significant differences in median time to progression or median survival between docetaxel (D; n = 161) and doxorubicin (DX; n = 165; 75 mg/m² every three weeks) on intent to treat and evaluable patient analyses. For the intent to treat analysis, median time to progression was 5.9 months for docetaxel and 4.9 months for doxorubicin (D-DX diff: 1.0 month; 95% confidence interval (CI) for diff: -0.5 to 1.9); median overall survival was 14.7 months for docetaxel and 14.3 months for doxorubicin (D-DX diff: 0.4 months; 95% CI for diff: -1.9 to 2.7). There was a significant difference in response rates between the two groups: 47.8% for docetaxel and 33.3% for doxorubicin (D-DX diff: 14.5%, 95% CI for diff: 3.9 to 25.0) in the intent to treat analysis.
In anthracycline failure patients, docetaxel (n = 203) was compared to the combination of mitomycin C and vinblastine (MV; n = 189; 12 mg/m² every six weeks and 6 mg/m² every three weeks, respectively). For the intent to treat analysis, docetaxel increased response rate (30% versus 11.6%; D-MV diff: 18.4%; 95% CI for diff: 10.6 to 26.2), prolonged median time to progression (4.3 months versus 2.5 months; D-MV diff: 1.8 months; 95% CI for diff: 1.0 to 2.4) and prolonged median overall survival (11.5 months versus 8.7 months; D-MV diff: 2.8 months; 95% CI for diff: 0.1 to 4.3). Similar results were observed in the evaluable patient analysis.
An open label, multicentre, randomised phase III study was conducted to compare docetaxel and paclitaxel in the treatment of advanced breast cancer in patients whose previous therapy should have included an anthracycline. A total of 449 patients were randomised to receive either docetaxel 100 mg/m² as a one hour infusion or paclitaxel 175 mg/m² as a three hour infusion. Both regimes were administered every three weeks. Efficacy results are described in Table 12.

The most frequent adverse events reported for docetaxel were neutropenia, febrile neutropenia, gastrointestinal disorders, neurological disorders, asthenia and fluid retention. More grade 3/4 events were observed from docetaxel (55.4%) compared to paclitaxel (23.0%). No unexpected toxicities were reported for docetaxel.
Combination with capecitabine. Docetaxel in combination with capecitabine was assessed in an open label, multicentre, randomised trial. A total of 511 patients with locally advanced and/or metastatic breast cancer resistant to, or recurring after an anthracycline containing therapy, or relapsing during or recurring within two years of completing an anthracycline containing adjuvant therapy were enrolled. In this trial, 255 patients were randomised to receive capecitabine (1,250 mg/m² twice daily for two weeks followed by a one-week rest period) in combination with docetaxel (75 mg/m² as a one-hour intravenous infusion every three weeks). 256 patients received docetaxel 100 mg/m² alone.
Docetaxel in combination with capecitabine resulted in statistically significant improvements in time to disease progression, overall survival and objective response rate compared to monotherapy with docetaxel as shown in Table 13. Health related quality of life (HRQoL) was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC-QLQ), (C30 version 2, including Breast Cancer Module BR23). HRQoL was similar in the two treatment groups.

Combination with trastuzumab (HER2+). Docetaxel in combination with trastuzumab was studied for the treatment of patients with metastatic breast cancer whose tumours overexpress HER2 and who previously had not received chemotherapy for metastatic disease. One hundred and eighty six patients received docetaxel (100 mg/m²) with or without trastuzumab; 60% of patients received prior anthracycline based adjuvant chemotherapy. Docetaxel plus trastuzumab was efficacious in patients whether or not they had received prior adjuvant anthracyclines. The main test used to determine HER2 positivity in this pivotal trial was immunohistochemistry (IHC). A minority of patients were tested using fluorescence in situ hybridisation (FISH). In this trial, 87% of patients had disease that was IHC 3+, and 95% of patients entered had disease that was IHC 3+ and/or FISH positive. Efficacy results are summarised in Table 14.

Adjuvant treatment of breast cancer. Combination with doxorubicin and cyclophosphamide. Data from a multicentre open label randomised trial support the use of docetaxel for the adjuvant treatment of patients with node positive breast cancer and KPS (Karnofsky performance score) greater than or equal to 80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1,491 patients were randomised to receive either docetaxel 75 mg/m² administered one hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² (TAC arm), or doxorubicin 50 mg/m² followed by fluorouracil 500 mg/m² and cyclophosphamide 500 mg/m² (FAC arm). Both regimens were administered once every three weeks for six cycles. Docetaxel was administered as a one hour infusion; all other drugs were given as IV (intravenous) bolus on day 1. G-CSF was administered in both arms as secondary prophylaxis to patients who experienced febrile neutropenia, prolonged neutropenia or neutropenic infection. Patients in the docetaxel arm who continued to experience these reactions remained on G-CSF and had their dose reduced to 60 mg/m². Patients on the TAC arm received antibiotic prophylaxis with ciprofloxacin 500 mg orally b.i.d. (twice daily) for ten days starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with positive oestrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to five years. Adjuvant radiation therapy was prescribed according to guidelines in place at participating institutions and was given to 69% of patients who received TAC and 72% of patients who received FAC.
An interim analysis was performed with a median follow-up of 55 months. Significantly longer disease free survival for the TAC arm compared to the FAC arm was demonstrated. In the TAC arm, 23% of subjects had experienced disease progression, compared to 30% in the FAC arm. TAC treated patients had a 28% reduction in the risk of relapse compared to those treated with FAC (hazard ratio = 0.72, 95% CI (0.59 to 0.88), p = 0.001). Overall survival was also significantly longer in the TAC arm, with TAC treated patients having a 30% reduction in the risk of death compared to FAC (hazard ratio = 0.70, 95% CI (0.53 to 0.91), p = 0.008). In the TAC arm, 12% of patients had died compared to 17% on the FAC arm.
In the adjuvant breast cancer trial (TAX 316), docetaxel in combination with doxorubicin and cyclophosphamide was administered to 744 patients of whom 48 (6%) were 65 years of age or greater. The number of elderly patients who received this regimen was not sufficient to determine whether there were differences in safety and efficacy between elderly and younger patients.
TAC treated patient subsets according to prospectively defined major prognostic factors were analysed (see Table 15).

The beneficial effect of TAC was seen in both hormone receptor positive and negative patients.
Combination with doxorubicin, cyclophosphamide and trastuzumab and with carboplatin and trastuzumab (HER2+). The efficacy and safety of docetaxel in combination with trastuzumab was studied for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2 (with node positive and high risk node negative). A total of 3,222 women were randomised in the study, and 3,174 were treated with either: AC-T, AC-TH or TCH.

AC-T (control arm).

Doxorubicin 60 mg/m² IV in combination with cyclophosphamide 600 mg/m² IV every 3 weeks for 4 cycles, followed by docetaxel 100 mg/m² as a 1-hour IV infusion every 3 weeks for 4 cycles.

AC-TH.

Doxorubicin 60 mg/m² IV in combination with cyclophosphamide 600 mg/m² IV every 3 weeks for 4 cycles. Three weeks after the last cycle of AC, trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 5 was administered, followed by trastuzumab 2 mg/kg by IV infusion over 30 minutes weekly starting day 8 of cycle 5; and docetaxel 100 mg/m² administered by IV infusion over 1 hour on day 2 of cycle 5, then on day 1 every 3 weeks for a total of 4 cycles of docetaxel. Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1 year from the date of first administration).

TCH.

Trastuzumab 4 mg/kg loading dose by IV infusion over 90 minutes on day 1 of cycle 1 only, followed by trastuzumab 2 mg/kg by IV infusion over 30 minutes weekly starting on day 8 until three weeks after the last cycle of chemotherapy. Docetaxel 75 mg/m² was administered on day 2 of cycle 1, then on day 1 of all subsequent cycles by IV infusion over 1 hour followed by carboplatin (AUC 6 mg/mL/min) as a 30-60-minute IV infusion, for a total of six cycles of docetaxel and carboplatin. Beginning three weeks after the last cycle of chemotherapy, trastuzumab 6 mg/kg by IV infusion over 30 minutes was given every 3 weeks (for 1 year from the date of first administration).
The patients and disease characteristics at baseline were well balanced between the 3 treatment arms.
Disease free survival (DFS) was the primary endpoint, and overall survival (OS) was the secondary endpoint.
Results of the second interim analysis, performed with a median follow-up of 36 months, demonstrated that docetaxel and trastuzumab given concurrently as part of either an anthracycline based (AC-TH) or non-anthracycline based (TCH) adjuvant treatment regimens, for patients with HER2 positive operable breast cancer, statistically prolonged both DFS and OS compared with the control arm (AC-T). The AC-TH and TCH regimens significantly improved disease free survival compared with AC-T at the significance level of 0.003 required for the interim analysis. Overall survival was significantly better with AC-TH but not TCH compared to AC-T in the interim analysis. There was no statistically significant difference between the two trastuzumab containing arms AC-TH and TCH for DFS and OS. Efficacy results are summarised in Table 16.

There were 29% of patients with high risk node negative disease included in the study. The benefit observed for the overall population was irrespective of the nodal status. See Table 17.

Combination with cyclophosphamide. Docetaxel in combination with cyclophosphamide (TC) was investigated in a phase III randomised prospective clinical trial, in comparison with the standard treatment regimen of doxorubicin and cyclophosphamide (AC). Results of the trial were only available in the form of two published papers. A total of 1016 patients with operable stage I to III invasive breast cancer were randomly assigned to receive either four cycles of AC (60 and 600 mg/m² respectively every three weeks; n = 510), or four cycles of TC (75 mg and 600 mg/m² every three weeks; n = 506) as adjuvant chemotherapy after complete surgical excision of the primary tumour. Patients had to have a primary tumour of ≥ 1 cm and < 7 cm, and no evidence of metastatic disease. Neoadjuvant chemotherapy was not permitted.
Both treatment groups were well balanced for major prognostic factors; including age, race, stage, histology, hormone receptor status and nodal status. On completion of four cycles of chemotherapy (with or without radiotherapy) tamoxifen was administered to all patients with hormone receptor positive breast cancer for 5 years.
After median follow up of 5 years, the results demonstrated an improvement in disease free survival (DFS) for TC compared with AC. In the TC arm 435/506 (86%) remained alive and disease-free, compared to 408/510 (80%) in the AC arm (HR = 0.67; 95% CI 0.50 to 0.94; p = 0.015).

Non-small cell lung cancer.

Patients treated at 75 mg/m².

One phase II study was conducted in 20 previously untreated patients with locally advanced or metastatic non-small cell lung cancer. In this clinical trial, docetaxel was administered at a dose of 75 mg/m² given as a one-hour infusion every three weeks. The response rate was 10%.

Patients treated at 100 mg/m².

Six phase II studies were conducted in patients with locally advanced or metastatic non-small cell lung cancer. A total of 160 patients had received no prior chemotherapy (previously untreated) and 88 patients had received prior platinum based chemotherapy (previously treated) which included 37 patients who had progressive disease with platinum therapy (platinum refractory). In these clinical trials, docetaxel was administered at a dose of 100 mg/m² given as a one hour infusion every three weeks.
The 100 mg/m² dose is associated with higher toxicity.
In the intent to treat analysis on previously untreated patients, the overall response rate was 26.9% and in the previously treated population it was 17%. The survival time for all previously untreated patients or previously treated patients was nine and eight months, respectively.

Ovarian cancer.

Patients treated at 100 mg/m².

Docetaxel was studied in five uncontrolled trials in patients with advanced epithelial ovarian cancer who had failed previous treatment with cisplatin or carboplatin. These patients (n = 377) received docetaxel 100 mg/m² in a one-hour intravenous infusion every three weeks.
In the intent to treat analysis, median time to progression ranged from 9.2 to 13.1 weeks, median survival ranged from 7 to 10.3 months, overall response rate ranged from 8.3 to 24.0% and complete response rate ranged from 2.8 to 8.3%.

Prostate cancer.

The safety and efficacy of docetaxel in patients with androgen independent (hormone refractory) metastatic prostate cancer were evaluated in a randomised multicentre phase III trial. A total of 1,006 patients with KPS greater than or equal to 60 were randomised to the following treatment groups:
docetaxel 75 mg/m² every three weeks for ten cycles;
docetaxel 30 mg/m² administered weekly for the first five weeks in a six week cycle for five cycles;
mitozantrone 12 mg/m² every three weeks for ten cycles.
All three regimens were administered in combination with prednisone or prednisolone 5 mg twice daily, continuously.
Patients who received docetaxel every three weeks demonstrated significantly longer overall survival compared to those treated with mitozantrone (p = 0.0094). The increase in survival seen in the docetaxel weekly arm was not statistically significant compared to the mitozantrone control arm. Efficacy endpoints for the docetaxel three weekly arm versus the control arm are summarised in Table 18.

Head and neck cancer.

Induction therapy followed by radiotherapy (TAX 323). The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) were evaluated in a phase III, multicentre, open label, randomised trial (TAX 323). In this study, 358 previously untreated patients with locally advanced inoperable stage III/IV SCCHN and World Health Organization (WHO) performance status 0 or 1, were randomised to one of two treatment arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m² followed by cisplatin (P) 75 mg/m² on day 1, followed by fluorouracil (F) 750 mg/m² per day as a continuous infusion on days 1 to 5. The cycles were repeated every three weeks for four cycles. Patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines (TPF/RT). Patients on the comparator arm received cisplatin 100 mg/m² on day 1, followed by fluorouracil 1,000 mg/m² (PF) as a continuous infusion on days 1 to 5. The cycles were repeated every three weeks for four cycles. Patients whose disease did not progress received RT according to institutional guidelines (PF/RT). At the end of chemotherapy, with a minimal interval of four weeks and a maximal interval of seven weeks, patients whose disease did not progress received radiotherapy (RT) according to institutional guidelines.
Conventional locoregional radiotherapy was given to approximately 77% of the patients at a total dose of 66 to 70 Gy (1.8 to 2.0 Gy once a day, five days/week) while accelerated/ hyperfractionated regimens of radiation therapy were used in approximately 23% of patients (twice a day, with a minimum interfraction interval of six hours, five days/week).
A total of 70 Gy was recommended for accelerated regimens and 74 Gy for hyperfractionated schemes. Surgical resection was allowed following chemotherapy, before or after radiotherapy. The primary endpoint in this study, progression free survival (PFS), was significantly longer in the TPF arm compared to the PF arm, p = 0.0042 (median PFS: 11.4 versus 8.3 months, respectively) with an overall median follow-up time of 33.7 months. Median overall survival (OS) was significantly longer in favour of the TPF arm compared to the PF arm (median OS: 18.6 versus 14.5 months, respectively) with a 28% risk reduction of mortality, p = 0.0128. Patients with tumours of the nasopharynx and the nasal/ paranasal cavities were excluded from this study. Efficacy results are presented in Table 19.

Clinical benefit parameters.

Patients treated with TPF experienced significantly less deterioration of their global health score compared to those treated with PF (p = 0.01, using EORTC QLQ-C30).
The performance status scale for head and neck, designed to measure disturbances of speech and eating, was significantly in favour of TPF treatment.
The median time to first deterioration of WHO performance status was significantly (p = 0.0158) longer in the TPF arm (13.7 months; 95% CI: 10.7 to 21.0 months) compared to PF (8.3 months; 95% CI: 7.3 to 9.6 months). However, no significant difference in WHO performance status was apparent between the two arms (odds ratio = 0.96, 95% CI: 0.66 to 1.41). There was no difference in pain intensity in patients treated with TPF or PF.
Induction chemotherapy followed by chemoradiotherapy (TAX 324). The safety and efficacy of docetaxel in the induction treatment of patients with locally advanced (technically unresectable, low probability of surgical cure, or candidates for organ preservation) SCCHN was evaluated in a randomised, multicentre open label, phase III trial (TAX 324). Patients with tumours of the nasopharynx and nasal/ paranasal cavities were excluded from this study. In this study, 501 patients with locally advanced SCCHN, and a WHO performance status of 0 or 1 were randomised to one of two arms. Patients on the docetaxel arm received docetaxel (T) 75 mg/m² by IV infusion on day 1, followed by cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour IV infusion, followed by the continuous IV infusion of fluorouracil (F) 1,000 mg/m²/day from day 1 to day 4. The cycles were repeated every three weeks for three cycles. All patients who did not have progressive disease were to receive chemoradiotherapy (CRT) as per protocol (TPF/CRT). Patients on the comparator arm received cisplatin (P) 100 mg/m² administered as a 30-minute to three-hour IV infusion, followed by the continuous IV infusion of fluorouracil (F) 1,000 mg/m²/day from day 1 to day 5. The cycles were repeated every three weeks for three cycles. All patients who did not have progressive disease were to receive CRT as per protocol (PF/CRT).
Patients in both treatment arms were to receive seven weeks of CRT following induction chemotherapy with a minimum interval of three weeks and no later than eight weeks after start of the last cycle (day 22 to day 56 of last cycle). During radiotherapy, carboplatin (AUC 1.5) was given weekly as a one-hour IV infusion for a maximum of seven doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, five days per week for seven weeks, for a total dose of 70 to 72 Gy). Surgery on the primary site of disease and/or neck could be considered at any time following completion of CRT.
The primary efficacy endpoint in this study, OS was significantly longer (log rank test p = 0.0058) with the docetaxel containing regimen compared to PF (median OS: 70.6 versus 30.1 months, respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% CI = 0.54 to 0.90). The secondary endpoint PFS demonstrated a 29% risk reduction of progression or death and a 22-month improvement in median PFS (35.5 months for TPF and 13.1 for PF). This was also statistically significant with an HR of 0.71; 95% CI 0.56 to 0.90; log rank test p = 0.004. Efficacy results are presented in Table 20.

5.2 Pharmacokinetic Properties

Absorption.

DBL Docetaxel Concentrated Injection is administered by intravenous infusion. By definition, absorption is complete at the end of the infusion.

Distribution.

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 5 to 115 mg/m² in phase I studies. The kinetic profile of docetaxel is dose independent and consistent with a three compartment pharmacokinetic model with half-lives for the alpha, beta and gamma phases of 4 minutes, 36 minutes and 11.1 hours, respectively. The initial rapid decline represents distribution to the peripheral compartments and the late phase is due, in part, to a relatively slow efflux of docetaxel from the peripheral compartment. Following the administration of a 100 mg/m² dose given as a one-hour infusion, a mean peak plasma level of 3.7 microgram/mL was obtained with a corresponding area under the curve (AUC) of 4.6 hour.microgram/mL. Mean values for total body clearance and steady-state volume of distribution were 21 L/hour/m² and 113 L, respectively.

Metabolism and excretion.

A study of ¹⁴C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in both the urine and faeces following oxidative metabolism of the tert-butyl ester group; within seven days, the urinary and faecal excretion account for about 6 and 75% of the administered radioactivity, respectively. About 80% of the radioactivity (60% of the administered dose) recovered in faeces is excreted during the first 48 hours as one major and three minor inactive metabolites and very low amounts of unchanged drug.
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those estimated from phase I studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient. In a small number of patients (n = 23) with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST greater than or equal to 1.5 times the upper limit of normal, associated with alkaline phosphatase greater than or equal to 2.5 times the upper limit of normal), total clearance was lowered by, on average, 27% (see Section 4.2 Dose and Method of Administration). Docetaxel clearance was not modified in patients with mild to moderate fluid retention. No data are available in patients with severe fluid retention.
Docetaxel is more than 95% bound to plasma proteins. Dexamethasone did not affect protein binding of docetaxel.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the pharmacokinetics of docetaxel was observed.
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and the effect of docetaxel on the pharmacokinetics of capecitabine showed no effect of capecitabine on the pharmacokinetics of docetaxel (C_max and AUC) and no effect of docetaxel on the pharmacokinetics of the main capecitabine metabolite 5'DFUR.
The combined administration of docetaxel, cisplatin and fluorouracil in 12 patients with solid tumours had no influence on the pharmacokinetics of each individual drug.

5.3 Preclinical Safety Data

Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be active on some, but not all, cell lines overexpressing the p-glycoprotein, which is encoded by the multidrug resistance gene. In vivo, docetaxel is schedule independent and has a broad spectrum of experimental antitumour activity against advanced murine and human grafted tumours. Against transplantable murine tumours in vivo, docetaxel was synergistic with vincristine (administered at the same time), etoposide, cyclophosphamide or fluorouracil, but not with vincristine (administered 24 hours apart), cisplatin or doxorubicin.

Genotoxicity.

Docetaxel was not mutagenic in bacterial or CHO/ HPRT gene mutation assays, but induced chromosomal aberrations in the in vitro chromosome aberration assay and in the in vivo micronucleus test in the mouse.

Carcinogenicity.

The carcinogenic potential of docetaxel has not been studied. However, based upon its pharmacodynamic mechanism of action, docetaxel may be a carcinogen.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ethanol, citric acid, polysorbate 80, macrogol 300.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 25°C. Protect from light.

6.5 Nature and Contents of Container

DBL Docetaxel Concentrated Injection solution is available in 20 mg/2 mL, 80 mg/8 mL and 160 mg/16 mL single dose clear glass vials with elastomeric stoppers, aluminium seals and flip off caps.

Pack size.

20 mg/2 mL vial in single packs.
80 mg/8 mL vial in single packs.
160 mg/16 mL vial in single packs.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Chemical name: (2R,3S)-N-carboxy-3-phenylisoserine, N-tert-butyl ester, 13-ester with 5β, 20-epoxy-1,2α,4,7β,10β,13α -hexahydroxytax-11-en-9-one 4- acetate 2-benzoate.
Molecular formula: C₄₃H₅₃NO₁₄.
Molecular weight: 807.88.
Docetaxel is a white to almost white powder. It is highly lipophilic and practically insoluble in water.

CAS number.

114977-28-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

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DBL Docetaxel Concentrated Injection

Docetaxel

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