Consumer medicine information

Docetaxel Accord

Docetaxel

BRAND INFORMATION

Brand name

Docetaxel Accord

Active ingredient

Docetaxel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Docetaxel Accord.

SUMMARY CMI

DOCETAXEL ACCORD

Consumer Medicine Information (CMI) summary

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

1. Why am I being given Docetaxel Accord?

Docetaxel Accord contains the active ingredient Docetaxel. Docetaxel Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents. It is used to treat breast cancer, ovarian cancer, some types of lung cancer, head and neck cancer and prostate cancer. Docetaxel Accord works by stopping cells from growing and multiplying.

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

2. What should I know before I am given Docetaxel Accord?

Do not use if you have ever had an allergic reaction to any medicine containing docetaxel, paclitaxel or any of the ingredients listed at the end of the CMI.

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

For more information, see Section 2. What should I know before I am given Docetaxel Accord? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Docetaxel Accord and affect how it works.

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

4. How will I be given Docetaxel Accord?

Docetaxel Accord will be given to you by a doctor or a nurse.

More instructions can be found in Section 4. How will I be given Docetaxel Accord? in the full CMI.

5. What should I know while being given Docetaxel Accord?

Things you should do
  • Be sure to keep all your doctor's appointments.
  • Tell any other doctors, dentists, and pharmacists who treat you that you are being given Docetaxel Accord.
  • If you become pregnant while you are being given this medicine, tell your doctor immediately.
  • Avoid people who have infections.
  • Be careful when using a toothbrush, toothpick or dental floss.
  • 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.
Driving or using machinesBe careful driving or operating machinery until you know how Docetaxel Accord affects you.

For more information, see Section 5. What should I know while being given Docetaxel Accord? in the full CMI.

6. Are there any side effects?

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

Some of the very serious side effects are:

  • 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
  • convulsions, fits or seizures
  • 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
  • sudden swelling of the leg/arm which may be due to blood clots

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



FULL CMI

DOCETAXEL ACCORD

Active ingredient(s): Docetaxel


Consumer Medicine Information (CMI)

This leaflet provides important information about using Docetaxel Accord. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Docetaxel Accord.

Where to find information in this leaflet:

1. Why am I being given Docetaxel Accord?
2. What should I know before I am given Docetaxel Accord?
3. What if I am taking other medicines?
4. How will I be given Docetaxel Accord?
5. What should I know while being given Docetaxel Accord?
6. Are there any side effects?
7. Product details

1. Why am I being given Docetaxel Accord?

Docetaxel Accord contains the active ingredient Docetaxel. Docetaxel Accord belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear of these being called chemotherapy medicines.

Docetaxel Accord is used to treat breast cancer, ovarian cancer, some types of lung cancer, head and neck cancer and prostate cancer.

Docetaxel Accord works by stopping cells from growing and multiplying.

Docetaxel Accord may be used alone or in combination with other medicines to treat cancer.

Your doctor, however, may prescribe Docetaxel Accord for another purpose.

2. What should I know before I am given Docetaxel Accord?

Warnings

You must not be given Docetaxel Accord if:

  • you have an allergy to docetaxel, paclitaxel or any of the ingredients listed at the end of this leaflet.
  • severe liver problems
  • you are pregnant or intend to become pregnant either during treatment or in the three months following the last dose of Docetaxel Accord

Docetaxel Accord is not recommended for use in children.

Tell your doctor if you have or have had:

  • liver problems
  • blood disorder with a reduced number of white blood cells
  • epilepsy
  • an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone

Tell your doctor if you plan to have surgery.

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

Pregnancy and breastfeeding

Tell your doctor if you:

  • are pregnant, or intend to become pregnant
  • are breastfeeding or plan to breastfeed

Like most medicines used to treat cancer, Docetaxel Accord is not recommended for use during pregnancy. Your doctor will discuss with you the risks and benefits of having Docetaxel Accord during pregnancy.

You should not breast-feed your child during your treatment with Docetaxel Accord. Docetaxel Accord may pass into breast milk and therefore there is a possibility that the breast-fed baby may be affected.

3. What if I am taking other medicines?

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

Some medicines and Docetaxel Accord 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
  • ketoconazole - a medicine used to treat fungal infections
  • nifedipine - medicine used to treat high blood pressure and angina

These medicines and treatments may be affected by Docetaxel Accord or may affect how well it works. You may need different amounts of your medicine, or you may need to have different medicines. Your doctor or pharmacist will advise you.

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

4. How will I be given Docetaxel Accord?

Before you are given your Docetaxel Accord infusion your doctor should:

  • Prescribe you an oral corticosteroid (e.g. dexamethasone) to help stop or reduce the severity of certain side effects. For breast, lung, ovarian, and head and neck, 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 Accord infusion at that time

How much will be given

Your doctor will decide on what dose you will receive. This depends on your condition and other factors, such as your weight and height.

The standard dose of Docetaxel Accord is 75 to 100mg/m2 which is based on your body size (m2).

When will Docetaxel Accord be given

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

Docetaxel Accord 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 receive too much Docetaxel Accord

Since Docetaxel Accord is usually given to you in hospital under the supervision of your doctor, it is very unlikely that you will be given too much of the medicine. If you think that you have been given too much Docetaxel Accord.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, nurse or pharmacist.

5. What should I know while being given Docetaxel Accord?

Things you must do

Be sure to keep all your doctor's appointments.

It is important to have your follow-up doses/cycles of Docetaxel Accord at the appropriate times to get the best effects from your treatments.

Your doctor may also 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.

Docetaxel Accord 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 or nurse immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, pain in the lower back or side or you 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 Accord 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.

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are being given Docetaxel Accord.

Tell any other doctors, dentists, and pharmacists who treat you that you are being given Docetaxel Accord.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are being given Docetaxel Accord.

If you become pregnant while you are being given Docetaxel Accord, tell your doctor immediately.

Driving or using machines

Be careful driving or operating machinery until you know how Docetaxel Accord affects you.

Looking after your medicine

The hospital will store Docetaxel Accord under the correct conditions.

Getting rid of any unwanted medicine

Your doctor or pharmacist will dispose of any Docetaxel Accord that may be left over.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

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

Common side effects

Less serious side effectsWhat to do
  • 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 or weakness not caused by exercise
  • unusual tiredness or weakness
  • confusion
  • mild swelling of hands, ankles and feet
  • weight gain
  • 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 Accord
Speak to your doctor if you have any of these common side effects and they worry you

Serious side effects

Serious side effectsWhat to do
  • infections
  • frequent infections with fever, severe chills, sore throat or mouth ulcers - especially 5-7 days after receiving a Docetaxel Accord 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
  • breathing problems, shortness of breath or difficulty in breathing
  • coughing, wheezing
  • change in the rhythm or rate of your heart beats (palpitations)
  • pain in muscles
  • flushed, dry skin, irritability and confusion
  • passing little or no urine, drowsiness, nausea, vomiting and breathlessness
  • fainting
  • 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
  • chest pain / heart attack
  • 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
Call your doctor straight away

Very Serious side effects

Very serious side effectsWhat to do
  • 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
  • convulsions, fits or seizures
  • 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
  • sudden swelling of the leg/arm which may be due to blood clots
Call your doctor straight away or go straight to the Emergency Department at your nearest hospital

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

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

Other side effects not listed above may occur in some patients.

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

Reporting side effects

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

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

7. Product details

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

It is not addictive.

What Docetaxel Accord contains

Active ingredient
(main ingredient)
docetaxel
Other ingredients
(inactive ingredients)
citric acid
ethanol anhydrous
polysorbate 80

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

Docetaxel Accord does not contain gluten, sucrose, lactose, tartrazine or any other azo dyes.

What Docetaxel Accord looks like

Docetaxel Accord is a pale yellow to brownish-yellow solution supplied in a vial in single packs. (80 mg/4 mL: AUST R 209473, 160 mg/8 mL: AUST R 209465)

Who distributes Docetaxel Accord

Accord Healthcare Pty Ltd
Level 24, 570 Bourke Street
Melbourne, VIC, 3000
Australia

This leaflet was prepared in May 2022.

Published by MIMS June 2022

BRAND INFORMATION

Brand name

Docetaxel Accord

Active ingredient

Docetaxel

Schedule

S4

 

1 Name of Medicine

Docetaxel.

2 Qualitative and Quantitative Composition

Each mL of docetaxel solution contains 20 mg docetaxel.
Docetaxel is a white to off white powder and it is highly lipophilic and practically insoluble in water.
Single-dose vials of Docetaxel Concentrated Injection containing 80 mg or 160 mg of docetaxel per 4.0 mL or 8.0 mL, respectively. The sterile pyrogen-free viscous solution contains 20 mg/mL docetaxel (anhydrous).
Each mL of docetaxel solution also contains 395 mg absolute ethanol. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Docetaxel Accord is a sterile pyrogen-free non-aqueous pale yellow to brownish-yellow solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Breast cancer.

Docetaxel Accord is indicated for the treatment of patients with locally advanced or metastatic breast cancer in whom previous chemotherapy has failed.
Docetaxel Accord 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.
Docetaxel Accord 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.

Docetaxel Accord in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with node-positive breast cancer.
Doxorubicin and cyclophosphamide followed by Docetaxel Accord in combination with trastuzumab (AC-TH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2.
Docetaxel Accord in combination with carboplatin and trastuzumab (TCH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2.
Docetaxel Accord 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.

Docetaxel Accord is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer, including those who have failed platinum-based chemotherapy.

Ovarian cancer.

Docetaxel Accord is indicated for the treatment of metastatic carcinoma of the ovary after failure of first-line or subsequent chemotherapy.

Prostate cancer.

Docetaxel Accord is indicated for the treatment of patients with androgen independent (hormone refractory) prostate cancer.

Head and neck cancer.

Docetaxel Accord, in combination with cisplatin and fluorouracil, 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

Recommended dosage.

Breast cancer. Metastatic breast cancer.

Monotherapy.

The recommended dosage of docetaxel 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 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 docetaxel 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 docetaxel 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 docetaxel 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 (see Dosage adjustments during treatment; see Section 4.4 Special Warnings and Precautions for Use, Haematology).

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 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 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 is docetaxel 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 docetaxel and continuing for a total of five doses.
Non-small cell lung cancer. The recommended dosage of docetaxel 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 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 docetaxel 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 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 docetaxel 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 docetaxel is 75 mg/m2 as a one hour infusion followed by cisplatin 75 mg/m2 over one hour, on day one, followed by fluorouracil as a continuous infusion at 750 mg/m2 per day for five days. This regimen is administered every 3 weeks for 4 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 docetaxel is 75 mg/m2 as a 1 hour intravenous infusion on day 1, followed by cisplatin 100 mg/m2 administered as a 30 minute to 3 hour infusion, followed by fluorouracil 1000 mg/m2 as a continuous infusion from day 1 to day 4. This regimen is administered every 3 weeks for 3 cycles. Following chemotherapy, patients should receive chemoradiotherapy.

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

A premedication consisting of an oral corticosteroids, such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 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.

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, 3 hours and 1 hour before the docetaxel infusion.

Dosage adjustments during treatment.

Docetaxel should be administered when the neutrophil count is ≥ 1.5 cells x 109/L.
In patients treated at 75 mg/m2. Patients who experienced either febrile neutropenia, neutrophil < 0.5 cells x 109/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, neutrophil < 0.5 cells x 109/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, the dosage should either 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 0-1, 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 0-1, 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. For the docetaxel plus trastuzumab combination, the recommended docetaxel dose is 100 mg/m2 every three weeks, with trastuzumab administered weekly. For trastuzumab dosage and administration, see the trastuzumab Product Information.
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 > 1500 cells/mm3 and platelets recover to a level > 100, 000 cells/mm3. Discontinue treatment if these toxicities persist.
For cisplatin and fluorouracil dosage and administration, see the relevant Product Information leaflet.
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 treated at 75 mg/m2.

For those patients with increased serum bilirubin and/or values > 3.5 times the ULN for ALT and AST and > 6 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 upper limit of normal range (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 > 6 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 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.
Children. The safety and effectiveness of docetaxel in children have not been established.
Elderly. Based on the population pharmacokinetics, there are no special instructions for the use in elderly. For capecitabine dosage reduction when combined with docetaxel, see capecitabine Product Information.

Monitoring advice.

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

Preparation and storage of the infusion solution.

Docetaxel concentrated injection is for single use in one patient only. Discard any unused residue.
More than one concentrate vial may be necessary to obtain the required dose for the patient.
Based on required dose for the patient expressed in mg, using a 21 gauge needle, aseptically withdraw the corresponding volume of Docetaxel Concentrate solution (20 mg/mL) from the appropriate number of concentrate vials using a single calibrated syringe fitted with a needle [for example, a dose of 140 mg docetaxel would require 7 mL of docetaxel concentrate solution]. Inject the required concentrate volume via a single injection (one shot) into a 250 mL infusion bag or bottle containing either 5% glucose solution or 0.9% sodium chloride solution. If a dose greater than 200 mg of docetaxel is required, use a larger volume of the infusion vehicle so that a concentration of 0.74 mg/mL docetaxel is not exceeded. Mix the infusion bag or bottle manually using a rocking motion.

Note.

The one shot technique reduces the number of needle insertions into the infusion bag hence minimising the risk of crystallisation.
Although chemical and physical stability of the diluted docetaxel solution for infusion prepared as recommended in 0.9% sodium chloride and 5% glucose solution in non-PVC bags has been demonstrated for up to 6 hours at 20 - 25°C and for 24 hours when stored between 2 - 8°C, the product contains no antimicrobial preservative.
To reduce microbiological hazard and crystallization of docetaxel, use as soon as practicable after dilution. If storage is necessary, hold at 2 - 8°C for not more than 24 hours (including the time to allow the infusion solution to return to room temperature before infusion).
Docetaxel infusion solution is supersaturated, therefore may crystallise over time. If crystals appear, the solution must no longer be used and should be discarded.
Any residue after infusion should be discarded. Any solutions which are discoloured, hazy or contain visible particulate matter should not be used.

4.3 Contraindications

Docetaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel or any of the excipients.
Docetaxel should not be used in patients with baseline neutrophil count of < 1.5 cells x 109/L.
Docetaxel should not be used in patients with severe liver impairment.
Docetaxel should not be used in pregnant or breast-feeding women.
Contraindications that apply for other drugs also apply when these drugs are combined with docetaxel.

4.4 Special Warnings and Precautions for Use

The use of docetaxel 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 docetaxel administration. A premedication consisting of an oral corticosteroid such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days starting one day prior to docetaxel administration can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions (see Fluid retention and Hypersensitivity reactions sections below) (see Section 4.2 Dose and Method of Administration).
For prostate cancer, the premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion.

Haematology.

Bone marrow suppression and other haematologic effects to docetaxel include neutropenia, the most frequent adverse reactions 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 ≥ 1.5 cells x 109/L.
Docetaxel should not be administered to patients with baseline neutrophil counts of less than < 1.5 cells x 109/L. Frequent monitoring of complete blood counts should be conducted on all patients during treatment with docetaxel. Patients should not be retreated with docetaxel until neutrophils recover to a level ≥ 1.5 cells x 109/L. (See Section 4.2 Dose and Method of Administration.)
In the case of severe neutropenia (< 0.5 cells x 109/L for seven days or more) during a course of docetaxel therapy, a reduction in dose for subsequent courses of therapy or the use of appropriate symptomatic measures are 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 docetaxel dose reduced (see also 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. 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 (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)).

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, during or immediately following the cessation of the infusion of docetaxel, 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 docetaxel 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 docetaxel.
Patients who have previously experienced a hypersensitivity reaction to paclitaxel may develop a potentially fatal 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 with oedema 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 such as eruptions followed by desquamation which rarely led to interruption or discontinuation of docetaxel treatment were reported. Nail disorders were characterised by hypo- or hyperpigmentation, pain and onycholysis.
Very rare cases of cutaneous lupus erythematosus and bullous eruptions such as erythema multiforme, scleroderma-like changes and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis 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.

Fluid retention.

A premedication consisting of an oral corticosteroid such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 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 kgs 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.

Nervous system.

The development of severe neurosensory signs and/or symptoms have been observed in patients and requires a reduction of dose (see Section 4.2 Dose and Method of Administration).
The amount of ethanol in Docetaxel Accord should be taken into account when given to patients with epilepsy (see Section 6.1 List of Excipients).
Consideration should be given to possible effects on the central nervous system.

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.

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.
Ventricular arrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with docetaxel in combination regimens including doxorubicin, fluorouracil and/or cyclophosphamide (see Section 4.8 Adverse Effects (Undesirable Effects)).
Prescribers should inform patients to report any irregular and/or rapid heartbeat, severe shortness of breath, dizziness, and/or fainting.

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).

Eye disorders.

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

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 Dose and Method of Administration).

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.

Docetaxel contains ethanol.
The alcohol content is harmful to those suffering from alcoholism.
The alcohol content is to be taken into account in pregnant or breast-feeding women, children and highrisk 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.

Recommendations for safe handling.

Docetaxel 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 docetaxel concentrate or infusion solution comes into contact with the skin, wash immediately and thoroughly with soap and water. If docetaxel concentrate or infusion solution comes into contact with mucous membranes, wash immediately and thoroughly with water.

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 (ULN) and increases in alkaline phosphatase > 2.5 times the ULN, there is a greater risk of developing severe adverse reactions 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 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. The amount of ethanol in Docetaxel Accord should be taken into account when given to patients with hepatic impairment (see Section 6.1 List of Excipients).

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 reactions, treatment-related serious adverse reactions and early withdrawals from treatment due to adverse reactions 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. ≥ 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 TAX323 and TAX324 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.

See Section 4.2 Dose and Method of Administration, Special populations, Children.

Effects on laboratory tests.

See Section 4.8 Adverse Effects (Undesirable Effects).

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, α1-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 ethanol in Docetaxel Accord may alter the effects of other medicinal products.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in mice have shown that IV doses of 144 mg/m2 or 30 mg/m2/day for 5 days are associated with testicular atrophy, mineralisation and degeneration of tubular germinal epithelium, Leydig cell hyperplasia, 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 IV doses of 0.9 mg/m2/day to both sexes are associated with reduced litter averages for corpora lutea, implantations and live fetuses, 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 body weight.
(Category D)
Drugs which have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations of irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
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 (IV) administration of radiolabelled docetaxel to pregnant rats. Docetaxel has been shown to be embryo- and fetotoxic in rats and rabbits. At IV doses of 0.9 mg/m2, docetaxel caused fewer corpora lutea, fewer implantations, increased resorptions and embryofetal deaths in rats. No evidence of teratogenic effects was found when docetaxel was administered IV 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 IV 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 appraised 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 IV 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 breast-feed during treatment with docetaxel and for one 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 Accord 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 of 2.0 m2) contains approximately 4.0 grams of absolute ethanol.

4.8 Adverse Effects (Undesirable Effects)

Clinical studies.

Monotherapy.

Breast, non-small cell lung and ovarian cancer. The adverse reactions 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 2106 (2045 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 3 weeks independently of the pre-medication. 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 reactions data:
35 toxic deaths (1.7%) were reported in the 2045 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 occur 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 haematologic adverse reactions to docetaxel include:
Neutropenia (in patients who did not receive G-CSF), the most frequent adverse reactions, was reversible and not cumulative. The median day to nadir was 7 days and the median duration of severe neutropenia was 7 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 multi-organ failure, has been reported.

Neurological.

Mild to moderate neuro-sensory signs and/or symptoms occurred in 50% of the patients. Severe neurosensory symptoms (paraesthesia, dysesthesia, 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) 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 reaction profile is consistent with the known toxicities of monotherapy treatments.
The most frequent treatment-related adverse reactions (≥ 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 reactions. The percentages of patients requiring dose reductions due to adverse reactions 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 reactions, as described for capecitabine monotherapy, can be expected for combination therapy as well. Refer to capecitabine Product Information for adverse reactions which are at least remotely related to capecitabine occurring in < 5% of patients treated with capecitabine in combination with docetaxel.
Combination with trastuzumab (HER 2+). Table 5 displays adverse events (all Grades) which were reported in ≥ 10% of patients treated with docetaxel in combination with trastuzumab for metastatic breast cancer.
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 3 weeks in combination with doxorubicin and cyclophosphamide and 736 patients, treated with the comparator study drugs.
Of the 744 patients treated with TAC, 33.1% experienced severe TEAEs. Dose reductions due to haematological toxicity occurred in 1% of cycles in TAC arm. Six percent 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 during the study period.

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, asthenia 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 and 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, Clinical trials). 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. 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 reaction profile is consistent with the known safety profile of docetaxel.
Table 10 provides the percentage of subjects with clinically important treatment-emergent adverse events (TEAEs) and haematological toxicities related to study treatment, reported in the phase III clinical trial for docetaxel 75 mg/m2 q3w 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 patients (TAX 323) and 251 patients (TAX 324) with locally advanced squamous cell carcinoma of the head and neck (SCCHN) who were treated with docetaxel 75 mg/m2 in combination with cisplatin and fluorouracil.

Post marketing reactions.

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 ≥ 1-10%, uncommon 0.1-1%; rare 0.01-0.1%; 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: anaphylactic shock resulted in a fatal outcome in patients who received premedication.
Hypersensitivity reactions such as bronchospasm and generalized rash have been reported.
Hypersensitivity reactions with potential fatal outcome 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 enterocolitisa, colitisa including ischemic colitisa, 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 arrhythmiab, congestive heart failure.
Rare: atrial fibrillation, syncope, tachycardiab.
Very rare: myocardial infarction, deep vein thrombosis, 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, 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, have 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 anti-tumour 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, respiratory failure, and radiation recall phenomena have rarely been reported, and may be associated with fatal outcome. Rare cases of radiation pneumonitis have been reported in patients receiving concomitant therapy.
Respiratory failure has been reported.

Musculoskeletal and connective tissue disorders.

Myositis has been reported.

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.

Blood 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.

Renal and urinary disorders.

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

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 http://www.tga.gov.au/reporting-problems (Australia) or https://nzphvc.otago.ac.nz/reporting/ (New Zealand).

4.9 Overdose

Symptoms.

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

Treatment.

In case of overdose, 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 overdose. The primary anticipated complications of overdose 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 Poison Information Centre on 13 11 26 (Australia) or the national Poisons Centre, 0800 POISON or 0800 764 766 (New Zealand).

5 Pharmacological Properties

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.

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.

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 75 mg/m2 dose in 55 previously untreated patients and 100 mg/m2 in 117 previously untreated and 111 previously treated patients. In these trials, docetaxel was administered as a one-hour infusion every 3 weeks.
Patients treated at 75 mg/m2. In the intent-to-treat analysis on previously untreated patients, the overall response rate (ORR) was 47% with 9% complete responses (CR). 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 ≤ 2 organs involved, the response rate was 58.6% and in patients with ≥ 3 organs involved 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 (ORR) was 56% with 9.4% complete responses (CR). The ORR was 48.6% with 3.6% CR in the previously treated population including 48.2% ORR with 3.6% CR 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 pretreated patients and 53.1% in the subgroup of 49 anthracycline resistant patients).
In patients with ≥ 3 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, 63.6% in previously treated and 63.2% in the subgroup of anthracycline resistant patients).

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 3 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 3 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 months; 95% 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 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 6 weeks and 6 mg/m2 every 3 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 docetaxel 100 mg/m2 as a one-hour infusion or paclitaxel 175 mg/m2 as a 3-hour infusion. Both regimes were administered every 3 weeks. Efficacy results are described in Table 12.
The most frequent adverse events reported for docetaxel were neutropenia, febrile neutropenia, gastrointestinal disorders, neurologic 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 (1250 mg/m2 twice daily for 2 weeks followed by a 1 week rest period) in combination with docetaxel (75 mg/m2 as a 1 hour intravenous infusion every 3 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 randomized trial support the use of docetaxel for the adjuvant treatment of patients with node-positive breast cancer and KPS ≥ 80%, between 18 and 70 years of age. After stratification according to the number of positive lymph nodes (1-3, 4+), 1491 patients were randomized to receive either docetaxel 75 mg/m2 administered 1 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 3 weeks for 6 cycles. Docetaxel was administered as a 1 hour infusion, all other drugs were given as IV 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. for 10 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 5 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 (0.59-0.88), 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 (0.53-0.91), 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 (TAX316), 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 in 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% Cl 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 75 mg/m2 dose given as a one-hour infusion every 3 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 100 mg/m2 dose given as a one-hour infusion every 3 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 (ORR) 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 9 and 8 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 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 1006 patients with KPS ≥ 60 were randomised to the following treatment groups:
Docetaxel 75 mg/m2 every 3 weeks for 10 cycles.
Docetaxel 30 mg/m2 administered weekly for the first 5 weeks in a 6 week cycle for 5 cycles.
Mitozantrone 12 mg/m2 every 3 weeks for 10 cycles.
All 3 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 3 weekly arm versus the control arm are summarised in Table 18.

Head and neck cancer.

Induction chemotherapy followed by radiotherapy (TAX323). The safety and efficacy of docetaxel in the induction treatment of patients with squamous cell carcinoma of the head and neck (SCCHN) was 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 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 1-5. The cycles were repeated every three weeks for 4 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 1000 mg/m2 (PF) as a continuous infusion on Days 1-5. The cycles were repeated every three weeks for 4 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 4 weeks and a maximal interval of 7 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 - 70 Gy (1.8 Gy - 2.0 Gy once a day, 5 days per week) while accelerated/hyperfractionated regimens of radiation therapy were used in approximately 23% of patients (twice a day, with a minimum interfraction interval of 6 hours, 5 days per 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 vs. 8.3 months respectively) with an overall median follow up time of 33.7 months. Median overall survival was significantly longer in favour of the TPF arm compared to the PF arm (median OS: 18.6 vs. 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 - 21.0 months) compared to PF (8.3 months; 95% CI: 7.3 - 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 - 1.41). There was no difference in pain intensity in patients treated with TPF or PF.
Induction chemotherapy followed by chemoradiotherapy (TAX324). 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 (TAX324). 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) 1000 mg/m2/day from day 1 to day 4. The cycles were repeated every 3 weeks for 3 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) 1000 mg/m2/day from day 1 to day 5. The cycles were repeated every 3 weeks for 3 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 7 weeks of CRT following induction chemotherapy with a minimum interval of 3 weeks and no later than 8 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 7 doses. Radiation was delivered with megavoltage equipment using once daily fractionation (2 Gy per day, 5 days per week for 7 weeks, for a total dose of 70 - 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, overall survival (OS) was significantly longer (log-rank test p = 0.0058) with the docetaxel-containing regimen compared to PF (median OS: 70.6 vs 30.1 months, respectively), with a 30% risk reduction in mortality compared to PF (hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.54 - 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 - 0.90; log-rank test p = 0.004. Efficacy results are presented in Table 20.

5.2 Pharmacokinetic Properties

Absorption.

No data available.

Distribution.

The pharmacokinetics of docetaxel have been evaluated in cancer patients after administration of 5-115 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 α, β and γ 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 AUC of 4.6 h.microgram/mL. Mean values for total body clearance and steady-state volume of distribution were 21 L/h/m2 and 113 L, respectively.

Metabolism.

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 ≥ 1.5 times the upper limit of normal associated with alkaline phosphatase ≥ 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 is 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 (Cmax 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.

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.

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 over expressing 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 was mutagenic in the in vitro chromosome aberration assay, in the in vivo micronucleus test in the mouse and modified the distribution of CHO-K1 cells in the cell cycle phases.

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

Each mL of docetaxel solution contains 4 mg citric acid, 395 mg absolute ethanol and 520 mg polysorbate 80.

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 and protect from light.

6.5 Nature and Contents of Container

Docetaxel Accord is supplied in single-dose type I glass vials with a fluorotec plus rubber stopper and flip-off seal. Two strengths are available containing docetaxel as follows: 80 mg/4 mL and 160 mg/8 mL in packs of 1.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Molecular Formula: C43H53NO14.
Molecular Weight: 807.88.
Chemical Name: (2R, 3S)- N-carboxy-3- phenylisoserine, N-tert- butyl ester, 13-ester with 5β, 20-epoxy1, 2α, 4, 7β, 10β, 13α- hexahydroxytax- 11-en-9-one 4-acetate 2-benzoate.

Chemical structure.


CAS number.

114977-28-5.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes