Consumer medicine information

Docetaxel Sandoz Concentrate for infusion

Docetaxel

BRAND INFORMATION

Brand name

Docetaxel Sandoz Concentrate for infusion

Active ingredient

Docetaxel

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Docetaxel Sandoz Concentrate for infusion.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Docetaxel Sandoz.

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

All medicines have risks and benefits. Your doctor has weighed the risks of you taking this medicine against the benefits they expect it will have for you.

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

Keep this leaflet.

You may need to read it again.

WHAT DOCETAXEL SANDOZ IS USED FOR

The name of the medicine is called Docetaxel Sandoz. It contains the active ingredient docetaxel. Docetaxel belongs to a group of medicines called antineoplastic or cytotoxic medicines. These may also be called chemotherapy medicines. It works by killing cancer cells and stopping cancer cells from growing and multiplying.

This medicine is used to treat

  • breast cancer
  • ovarian cancer
  • some types of lung cancer
  • head and neck cancer
  • prostate cancer.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed Docetaxel Sandoz for another reason.

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

This medicine is not addictive.

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

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

BEFORE YOU ARE GIVEN DOCETAXEL SANDOZ

When you must not be given Docetaxel Sandoz

Do not receive this medicine if you have an allergy to:

  • Docetaxel, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under Product Description.

Some of the symptoms of an allergic reaction may include:

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

Do not receive Docetaxel Sandoz if you have or have had any of the following medical conditions:

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

Do not receive this medicine if you are pregnant or intend to become pregnant either during treatment or in the three months following the last dose of docetaxel.

Like most medicines to treat cancer, this medicine is not recommended to be used during pregnancy. Your doctor will discuss the risks and benefits of being given it if you are pregnant.

Do not breastfeed if you are given this medicine.

It is not known whether the active ingredient in Docetaxel Sandoz passes into breast milk and there is a possibility that your baby may be affected. Your doctor will discuss the risks and benefits of being given it if you are breast feeding or are planning to breast feed.

Do not give this medicine to a child.

Safety and effectiveness in children have not been established.

Do not receive this medicine after the expiry date printed on the vial or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, it may not work as well.

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

Before you are given Docetaxel Sandoz

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

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

  • liver problems
  • blood disorder with a reduced number of white blood cells.

Tell your doctor if you have an infection or high temperature.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold, is not usually a reason to delay treatment.

Tell your doctor if you plan to have surgery.

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

Taking other medicines

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

Some medicines and Docetaxel Sandoz 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
  • medicines used to used to treat or prevent viral infections, including ritonavir.

These medicines and treatments may be affected by Docetaxel Sandoz, 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.

Your doctor, nurse or pharmacist has more information on medicines to be careful with or to avoid while being given Docetaxel Sandoz.

HOW DOCETAXEL SANDOZ IS GIVEN

Docetaxel Sandoz should only be administered by trained professionals, with appropriate handling, in a hospital or clinic environment. Each vial is single use, to be used for one patient only on one occasion only.

Before you are given your Docetaxel Sandoz 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 cancer, this medicine is usually received 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 Sandoz infusion at that time.

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

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

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

How much is given

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

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

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

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

How Docetaxel Sandoz is given

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

How long Docetaxel Sandoz will be given

Docetaxel Sandoz 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 (overdose)

As Docetaxel Sandoz is given to you under the supervision of your doctor, it is very unlikely that you will receive too much. However, if you experience any unexpected or worrying side effects after being given Docetaxel Sandoz, telephone your doctor or the Poisons Information Centre (telephone Australia 13 11 26 or New Zealand 0800 POISON or 0800 764766) for advice, or go to Accident and Emergency at the nearest hospital.

You may need urgent medical attention.

WHILE YOU ARE BEING GIVEN DOCETAXEL SANDOZ

Things you must do

Tell all the doctors, dentists and pharmacists who are treating you that you are being given Docetaxel Sandoz.

If you are about to be started on any new medicine, tell your doctor or pharmacist that you are being given Docetaxel Sandoz.

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

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

Docetaxel Sandoz 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 Sandoz 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.

Be sure to keep all your doctor's appointments.

It is important to have your follow-up doses/cycles/infusions of Docetaxel Sandoz 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.

Things you must not do

Do not have Docetaxel Sandoz to treat any other complaints unless your doctor tells you to.

Things to be careful of

The breakdown products may be excreted in body fluids and waste, including blood, urine, faeces, vomitus and semen.

In general, precautions to protect other people should be taken while you are receiving Docetaxel Sandoz by:

  • flushing the toilet twice (with the toilet lid down) to dispose of any body fluids and waste
  • wearing gloves to clean any spill of body fluid or waste. Use paper towels or old rags, a strong solution of non-bleaching detergent and large amounts of water to mop up the spill. Discard the towels or rags into a separate waste bag and dispose of fluids in the toilet
  • washing linen or clothing that is heavily contaminated by body fluids or waste separately from other items. Use a strong solution of non-bleaching detergent and large amounts of water
  • placing soiled disposable nappies and other pads in a plastic bag, seal and dispose into the garbage
  • for sexual intercourse, use a barrier method such as a condom.

SIDE EFFECTS

All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being given Docetaxel Sandoz.

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

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

  • irritation, pain, swelling or colouring around the needle during infusion
  • high temperature
  • stomach pain or discomfort
  • feeling sick, upset stomach or vomiting
  • mild diarrhoea
  • constipation
  • inflammation of the food pipe (oesophagus)
  • whitening or darkening of the skin or nails
  • loosening of the nails
  • unusual hair loss or thinning
  • joint pain or swelling
  • aching muscles, muscle tenderness 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 Sandoz.

These are the more common side effects of Docetaxel Sandoz.

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

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

Tell your doctor, nurse or pharmacist as soon as possible if you notice any of the following:

  • infections
  • frequent infections with fever, severe chills, sore throat or mouth ulcers - especially 5-7 days after receiving a Docetaxel Sandoz 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
  • 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.

These may be serious side effects. You may need medical attention.

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

  • sudden signs of allergy such as rash, itching, hives on the skin, swelling of the face, tongue or other parts of the body, shortness of breath, wheezing or trouble breathing
  • 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.

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

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

Tell your doctor, nurse or pharmacist if you notice anything else that is making you feel unwell.

Other side effects not listed above may also occur in some people.

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

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor to answer any questions you may have.

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

AFTER BEING GIVEN DOCETAXEL SANDOZ

If you have any queries about any aspect of your medicine, or any questions regarding the information in this leaflet, discuss them with your doctor, nurse or pharmacist.

Storage

The Docetaxel Sandoz concentrate for infusion will be stored in the pharmacy or on the ward. The infusion is kept in a cool dry place, where the temperature stays below 25°C.

Disposal

The hospital staff will dispose of any unused Docetaxel Sandoz.

PRODUCT DESCRIPTION

What it looks like

Docetaxel Sandoz comes in 2 types of vials:

  • Docetaxel Sandoz 20mg/2mL - 2mL clear glass vial with rubber stopper (latex free) and flip-off aluminium crimp, containing a clear pale yellow sterile solution.
  • Docetaxel Sandoz 80mg/8mL - 8mL clear glass vial with rubber stopper (latex free) and flip-off aluminium crimp, containing a clear pale yellow sterile solution.

Available in packs of 1 vial.

The Docetaxel Sandoz concentrated injection for infusion vial is injected into an infusion bag/glass bottle ready for your infusion in the Chemotherapy Unit. The infusion bag/glass bottle is then sent to the Chemotherapy Unit ready for your infusion.

Ingredients

Active ingredients:

  • Docetaxel Sandoz 20mg/2mL - 20mg docetaxel
  • Docetaxel Sandoz 80mg/8mL - 80mg docetaxel

Inactive ingredients:

  • Ethanol
  • Polysorbate 80
  • Citric Acid, anhydrous.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Your doctor, nurse or pharmacist can inform you what other ingredients are in your infusion bag/glass bottle.

Supplier

Sandoz Pty Ltd
ABN 60 075 449 553
Level 2, 19 Harris St
Pyrmont NSW 2009
Tel: 1800 634 500

Novartis New Zealand Ltd
Private Bag 65904 Mairangi Bay
Auckland 0754
New Zealand
Tel: 0800 354 335

This leaflet was prepared in October 2011.

Australian Register Numbers
Docetaxel Sandoz 20mg/2mL concentrated injection for infusion: AUST R 170108
Docetaxel Sandoz 80mg/8mL concentrated injection for infusion: AUST R 170109

BRAND INFORMATION

Brand name

Docetaxel Sandoz Concentrate for infusion

Active ingredient

Docetaxel

Schedule

S4

 

Name of the medicine

Docetaxel.

Excipients.

Each mL of Docetaxel Sandoz concentrated injection for infusion contains ethanol 590.85 mg, polysorbate 80 268.25 mg and anhydrous citric acid 1 mg.

Description

Chemical name: 1,7β, 10β-trihydroxy-9-oxo- 5β,20-epoxytax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3- [[(1,1-dimethylethoxy)carbonyl]amino] -2-hydroxy-3-phenylpropanoate]. Molecular formula: C43H53NO14. MW: 807.88. CAS: 114977-28-5. Docetaxel is a white to almost white powder. It is highly lipophilic and practically insoluble in water. The concentrated injection for infusion is a sterile clear, colourless to pale yellow solution free from visible particulates.
Single dose vials of Docetaxel Sandox concentrated injection for infusion contain either 20 mg or 80 mg of docetaxel, in 2.0 mL or 8.0 mL of solvent, respectively. The sterile pyrogen free viscous solution contains a concentration of 10 mg/mL docetaxel.

Pharmacology

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

Pharmacodynamics.

Docetaxel was found to be cytotoxic in vitro against various murine and human tumour cell lines and against freshly excised human tumour cells in clonogenic assays. Docetaxel achieves high intracellular concentrations with a long cell residence time. In addition, docetaxel was found to be active on some, but not all, cell lines overexpressing the ρ-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.

Pharmacokinetics.

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 and excretion.

A study of 14C-docetaxel has been conducted in three cancer patients. Docetaxel was eliminated in both the urine and faeces following oxidative metabolism of the tert-butyl ester group; within seven days, the urinary and faecal excretion account for about 6% and 75% of the administered radioactivity, respectively. About 80% of the radioactivity (60% of the administered dose) recovered in faeces is excreted during the first 48 hours as one major and three minor inactive metabolites and very low amounts of unchanged drug.
A population pharmacokinetic analysis has been performed with docetaxel in 577 patients. Pharmacokinetic parameters estimated by the model were very close to those estimated from phase I studies. The pharmacokinetics of docetaxel were not altered by the age or sex of the patient. In a small number of patients (n = 23) with clinical chemistry data suggestive of mild to moderate liver function impairment (ALT, AST ≥ 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 Dosage and Administration). Docetaxel clearance was not modified in patients with mild to moderate fluid retention. No data are available in patients with severe fluid retention. Docetaxel is more than 95% bound to plasma proteins. Dexamethasone did not affect protein binding of docetaxel.
The effect of prednisone on the pharmacokinetics of docetaxel administered with standard dexamethasone premedication has been studied in 42 patients. No effect of prednisone on the pharmacokinetics of docetaxel was observed.
Phase I studies evaluating the effect of capecitabine on the pharmacokinetics of docetaxel and the effect of docetaxel on the pharmacokinetics of capecitabine showed no effect of capecitabine on the pharmacokinetics of docetaxel (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.

Clinical Trials

Breast cancer and 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 at 100 mg/m2 dose 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, it was 29.4%. A significant response rate was seen in patients with liver metastases (45% in untreated patients). The same activity is maintained in untreated patients with soft tissue disease (55.5%).

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

In the intent to treat analysis on previously untreated patients, the overall response rate (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 patients, 63.6% in previously treated patients 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 either 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 1.
The most frequent adverse events reported for docetaxel were neutropenia, febrile neutropenia, gastrointestinal disorders, neurological disorders, asthenia and fluid retention. More grade 3/4 events were observed from docetaxel (55.4%) compared to paclitaxel (23.0%). No unexpected toxicities were reported for docetaxel.

Combination with capecitabine.

Docetaxel in combination with capecitabine was assessed in an open label, multicentre, randomised trial. A total of 511 patients with locally advanced and/or metastatic breast cancer resistant to, or recurring after an anthracycline containing therapy, or relapsing during or recurring within two years of completing an anthracycline containing adjuvant therapy were enrolled. In this trial, 255 patients were randomised to receive capecitabine (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 2. 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 3.

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 ten days starting on day 5 of each cycle, or equivalent. In both arms, after the last cycle of chemotherapy, patients with positive oestrogen and/or progesterone receptors received tamoxifen 20 mg daily for up to 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 (see Table 4).
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 nonanthracycline 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 5.
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 6.

Combination with cyclophosphamide.

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

Non-small cell lung cancer.

Patients treated at 75 mg/m2.

One phase II study was conducted in 20 previously untreated patients with locally advanced or metastatic non-small cell lung cancer. In this clinical trial, docetaxel was administered at a dose of 75 mg/m2 given as a one hour infusion every 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 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 summarized in Table 7.

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) were evaluated in a phase III, multicentre, open label, randomised trial (TAX323). 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 to 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 8.

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 9.

Indications

Breast cancer.

Metastatic breast cancer.

Docetaxel Sandoz is indicated for the treatment of patients with locally advanced or metastatic breast cancer in whom previous chemotherapy has failed.
Docetaxel Sandoz 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 Sandoz 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 Sandoz 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 Sandoz in combination with trastuzumab (AC-TH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2.
Docetaxel Sandoz in combination with carboplatin and trastuzumab (TCH) is indicated for the adjuvant treatment of patients with operable breast cancer whose tumours overexpress HER2.
Docetaxel 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 Sandoz 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 Sandoz is indicated for the treatment of metastatic carcinoma of the ovary after failure of firstline or subsequent chemotherapy.

Prostate cancer.

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

Head and neck cancer.

Docetaxel Sandoz, 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.

Contraindications

Docetaxel is contraindicated in patients who have a history of severe hypersensitivity reactions to docetaxel, polysorbate 80 or to any other ingredients of this medicine.
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 breastfeeding women.
Contraindications that apply for other medicines also apply when these medicines are combined with docetaxel.

Precautions

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 pretreated 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 reaction sections below; see also Dosage and 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 neutropoenia, the most frequent adverse effects of docetaxel (see Adverse 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 Dosage and Administration). In the case of severe neutropoenia (< 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 who receive adjuvant therapy for breast cancer and who experience febrile neutropoenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their docetaxel dose reduced (see also Dosage adjustments during treatment). In the treatment of adjuvant breast cancer, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up (see Adverse 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.

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, Stevens-Johnson syndrome, toxic epidermal necrolysis and scleroderma-like changes have been reported with docetaxel. 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 Dosage and 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 with liver 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) greater than 1.5 times the upper limit of normal (ULN) and increases in alkaline phosphatase greater than 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 neutropoenia, infections, thrombocytopoenia, stomatitis and asthenia. The recommended dose of docetaxel in patients with elevated LFTs is 75 mg/m2 (see Dosage and 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.

Nervous system.

The development of severe neurosensory signs and/or symptoms have been observed in patients and requires a reduction of dose (see Dosage and Administration).

Cardiac toxicity.

Heart failure has been observed in patients receiving docetaxel in combination with trastuzumab, particularly following anthracycline (doxorubicin and epirubicin) containing chemotherapy. This may be moderate to severe and has been associated with death.

Eye disorders.

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

Leukaemia.

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

Others.

Contraceptive measures must be taken by both men and women during treatment and for men at least 6 months after cessation of therapy.
Grapefruit (fruit or juice) consumption should be avoided.
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.

Gastrointestinal reactions.

Symptoms such as 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.
Use with caution in the following circumstances:

Effects on fertility.

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 foetuses, and increased litter averages for early and total resorptions. Larger doses to both sexes (males 1.8 mg/m2/day, females 1.35 mg/m2/day) are additionally associated with increased time to mating, increased number of dams with total resorption, and reduced male foetal body weight.

Use in pregnancy.

(Category D)
Docetaxel may cause foetal harm when administered to a pregnant woman. Therefore, docetaxel must not be used during pregnancy. Foetal radioactivity has been detected following intravenous (IV) administration of radiolabelled docetaxel to pregnant rats. Docetaxel has been shown to be embryo- and foetotoxic in rats and rabbits. At IV doses of 0.9 mg/m2, docetaxel caused fewer corpora lutea, fewer implantations, increased resorptions and embryofoetal deaths in rats. No evidence of teratogenic effects was found when docetaxel was administered IV at doses up to 1.8 mg/m2 or 1.2 mg/m2 in rats or rabbits, respectively, but reduced foetal weight and delayed ossification were observed.
Offspring from rats receiving docetaxel 1.5 mg/m2/day i.v. 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 medicine, she should be appraised of the potential hazard. Women of childbearing potential should be advised to avoid becoming pregnant during therapy with this medicine. Contraceptive measures must be taken during and for at least three months after cessation of therapy with docetaxel.

Use in lactation.

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 i.v. during late gestation and lactation showed signs of delayed development. It is not known whether docetaxel is excreted in human milk. It is recommended to advise women not to breastfeed during treatment with docetaxel.

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 effects compared to patients less than 60 years of age.
Of the 333 patients treated with docetaxel every three weeks 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.
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.

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.
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.

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

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 cyclosporin, 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 coadministration regimens.
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.
In case of grapefruit consumption as fruit or juice, the occurrence of docetaxel side effects may increase, as a result of increased intestinal bioavailability. Therefore, as long as docetaxel is given, grapefruit should be avoided.

Adverse Effects

Clinical studies. Monotherapy. Breast, non-small cell lung and ovarian cancer.

The adverse effects considered to be possibly or probably related to starting the administration of docetaxel have been obtained from 75 patients who received a dose of 75 mg/m2 without the recommended premedication, and from 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 premedication. The patients were enrolled in 40 phase II and III studies conducted in Europe and North America (991 with breast carcinoma, 668 with non-small cell lung carcinoma and 447 with various tumour types).
The safety profile is generally similar between patients receiving docetaxel for the treatment of breast, non-small cell lung or ovarian carcinoma.
Table 10 lists the adverse effects data:
Thirty five 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 (neutropoenic 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 Precautions).

Haematological.

Bone marrow suppression and other haematologic adverse effects to docetaxel include the following.
Neutropoenia (in patients who did not receive G-CSF), the most frequent adverse effect, was reversible and not cumulative. The median day to nadir was 7 days and the median duration of severe neutropoenia was 7 days.
Febrile neutropoenia and severe infections associated with neutrophil counts < 0.5 x 109/L, infectious episodes (severe including sepsis pneumonia, fatal in 1.7%), occurred.
Thrombocytopoenia, bleeding episodes (rarely associated with severe thrombocytopoenia) and anaemia (severe) were also reported.
Disseminated intravascular coagulation (DIC), often in association with sepsis, or multiorgan failure, has been reported.

Neurologic.

Mild to moderate neurosensory signs and/or symptoms occurred in 50% of the patients. Severe neurosensory symptoms (paresthesia, dysesthesia, pain including burning) were observed in 4.1% of metastatic breast cancer patients, and resulted in treatment discontinuation in 2%. Neuromotor 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 effects sometimes appear during the infusion of the medicine.

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 and metastatic breast cancer.

Combination with capecitabine.

The adverse effects profile is consistent with the known toxicities of monotherapy treatments. The most frequent treatment related adverse effects (≥ 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 11. The mean duration of treatment was 129 days in the combination arm and 98 days in the monotherapy arm. A total of 66 patients (26%) in the combination arm and 49 (20%) in the monotherapy arm discontinued from the trial because of adverse effects. The percentages of patients requiring dose reductions due to adverse effects were 65% in the combination arm and 36% in the monotherapy arm.
Frequent grade 3 and 4 laboratory abnormalities are listed in Table 12.
Rare or uncommon adverse effects, as described for capecitabine monotherapy, can be expected for combination therapy as well. See capecitabine product information for adverse effects which are at least remotely related to capecitabine occurring in < 5% of patients treated with capecitabine in combination with docetaxel.

Combination with trastuzumab (HER 2+).

Table 13 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 14:
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 15 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 haematologic 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.

Gastrointestinal events.

In addition to gastrointestinal events reflected in Table 15, 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.

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, amenorrhea, neurosensory and peripheral oedema.

Combination with doxorubicin, cyclophosphamide and trastuzumab and with carboplatin and trastuzumab (HER2+).

See Table 16.
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 Clinical Trials section). 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 17.

Prostate cancer.

Combination with prednisone or prednisolone.

The adverse effect profile is consistent with the known safety profile of docetaxel.
Table 18 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 19 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.

Postmarketing effects.

The following information relates to serious events observed following the marketing of docetaxel. Voluntary reports of serious adverse events that have been received since market introduction (without causal relationship) that are not listed previously are cited below. Frequency estimates are as follows: common ≥ 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: these cases resulted in a fatal outcome in patients who received premedication.

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.
Severe nail disorders characterised by hypopigmentation or hyperpigmentation, and infrequently onycholysis and pain. Cases of persisting alopecia have been reported.

Fluid retention.

Rare: dehydration and pulmonary oedema have been reported.

Gastrointestinal.

Rare: constipation, oesophagitis and taste perversion, gastrointestinal haemorrhage, dehydration as a consequence of gastrointestinal events. Very rare: duodenal ulcer, ileus and intestinal obstruction, gastrointestinal perforation, neutropoenic enterocolitis, colitis including ischemic colitis.

Neurologic.

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

Cardiovascular.

Common: hypertension, hypotension. Uncommon: cardiac arrhythmia, congestive heart failure. Rare: atrial fibrillation, syncope, tachycardia. Very rare: deep vein thrombosis, myocardial infarction, ECG abnormalities, thrombophlebitis, pulmonary embolism.

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.

Eye disorders.

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

Respiratory, thoracic and mediastinal disorders.

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

Haematological and lymphatic disorders.

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

Urogenital.

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

Metabolism and nutrition disorders.

Cases of hyponatraemia have been reported, mostly associated with dehydration, vomiting and pneumonia.

Other.

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

Dosage and Administration

Breast cancer and 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 for intravenous administration). 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. See 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 also Dosage adjustments during treatment and Precautions, 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 to the following schedule:
Cycle 1. Day 1: trastuzumab 4 mg/kg (loading dose); day 2: docetaxel 75 mg/m2 and carboplatin at AUC of 6 mg/mL/min; days 8 and 15: trastuzumab 2 mg/kg.
Cycles 2-6. Day 1: docetaxel 75 mg/m2 followed by carboplatin at AUC of 6 mg/mL/min and trastuzumab 2 mg/kg; days 8 and 15: trastuzumab 2 mg/kg.
Three weeks after day 1 of cycle 6: trastuzumab 6 mg/kg is given every three weeks.
Trastuzumab is administered for a total duration of 1 year.

Combination with cyclophosphamide.

The recommended dosage 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 for intravenous administration). 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 for intravenous administration). 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.

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 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.

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, neutrophils < 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, neutrophils < 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 (TAC).

In the docetaxel, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow-up (see Adverse Effects). 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 this reaction 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/m3. 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 20.

Infants and children.

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

Use in the elderly.

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

Use in patients with hepatic impairment.

In patients treated at 75 mg/m2.

For those patients with increased serum bilirubin and/or values > 3.5 times the 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 Pharmacokinetics). 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.

Preparation for intravenous administration.

Docetaxel Sandoz 20 mg/2 mL and 80 mg/8 mL vials.

Docetaxel Sandoz 20 mg concentrated injection for infusion vial contains 2 mL of a 10 mg/mL solution of docetaxel. Docetaxel Sandoz 80 mg concentrated injection for infusion vial contains 8 mL of a 10 mg/mL solution of docetaxel. The concentrated injection for infusion must be added to a 250 mL infusion bag or glass bottle containing either 0.9% sodium chloride solution or 5% glucose solution. Do not administer undiluted.

Preparation and storage of the infusion solution.

More than one concentrated injection for infusion vial may be necessary to obtain the required dose for each patient. Based on the required dose for the patient expressed in mg, aseptically withdraw the corresponding concentrated solution volume containing 10 mg/mL docetaxel from the appropriate number of vials using a graduated syringe fitted with a needle. For example, a dose of 140 mg docetaxel would require 14 mL of the docetaxel concentrated injection for infusion.
Inject the required concentrated injection for infusion into a 250 mL infusion bag or glass bottle containing either 0.9% sodium chloride solution or 5% glucose solution. A final infusion concentration of 0.30 mg/mL to 0.74 mg/mL is recommended. 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 glass bottle manually using a rocking motion.
As with all parenteral products, Docetaxel Sandoz concentrated injection for infusion should be visually inspected prior to use, and solutions containing a precipitate should be discarded.
Docetaxel Sandoz concentrated injection for infusion should be aseptically administered intravenously as a one hour infusion under room temperature and normal lighting conditions. Docetaxel Sandoz concentrated injection has been shown to be physically and chemically stable for up to 48 hours at either room temperature or under refrigeration at 2-8°C following dilution in 5% glucose or 0.9% sodium chloride injections fluid in either glass bottles or polyethylene bags. However, to reduce microbiological hazard, use as soon as practicable after dilution/ preparation. If storage is necessary, hold at 2-8°C for not more than 24 hours after preparation. Administration should be completed within 24 hours of preparation of the infusion and any residue discarded according to the guidelines for the disposal of cytotoxic medicines (see Handling and Disposal below). Docetaxel Sandoz is a supplied in single dose vials. Use in one patient on one occasion only. Any residue after infusion should be discarded. Any solutions which are discoloured, hazy or contain visible particulate matter should not be used.
When dilutions of Docetaxel Sandoz are prepared in PVC containers, extractable plasticiser DEHP [di-(2-ethylhexyl)phthalate] levels increase with time and Docetaxel Sandoz concentration. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Docetaxel Sandoz solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene lined, should be used.

Disposal.

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

Overdosage

Contact the Poisons Information Centre on 131 126 for advice on management of overdose.

Symptoms.

In case of overdosage, the patient should be kept in a specialised unit and vital functions closely monitored. There is no known antidote for docetaxel overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis.

Treatment.

Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed. 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.

Presentation

Concentrated injection for infusion (sterile, pyrogen free, colourless to pale yellow viscous solution), 20 mg/2 mL, 80 mg/8 mL: 1's (single dose clear glass vial with rubber stopper (latex free), flip-off aluminium crimp).

Storage

Store below 25°C.

Poison Schedule

S4.