Taxotere (Docetaxel) 20mg

1. WHAT TAXOTERE IS AND WHAT IT IS USED FOR

The name of this medicine is TAXOTERE. Its common name is docetaxel. Docetaxel is a substance derived from the needles of yew trees.
Docetaxel belongs to the group of anti-cancer medicines called taxoids.

TAXOTERE has been prescribed by your doctor for the treatment of breast cancer, special forms of lung cancer (non-small cell lung cancer), prostate cancer or gastric cancer:

• For the treatment of advanced breast cancer, TAXOTERE could be administered either alone or in combination with doxorubicin, or trastuzumab, or capecitabine.
• For the treatment of early breast cancer with lymph node involvement, TAXOTERE could be administered in combination with doxorubicin and cyclophosphamide.
• For the treatment of lung cancer, TAXOTERE could be administered either alone or in combination with cisplatin.
• For the treatment of prostate cancer, TAXOTERE is administered in combination with prednisone or prednisolone.
• For the treatment of metastatic gastric cancer, TAXOTERE is administered in combination with cisplatin and 5-fluorouracil.

2. BEFORE YOU USE TAXOTERE

You should not be given TAXOTERE if:

• you experienced in the past a severe allergic reaction to it or to polysorbate 80 which is contained in the product.
• the number of white blood cells is too low.
• you have a severe liver disease.
• you are pregnant or breast feeding.

Take special care with TAXOTERE:

Before each treatment with TAXOTERE, you will have blood tests to check that you have enough blood cells and sufficient liver function to receive TAXOTERE. In case of white blood cells disturbances, you may experience associated fever or infections.

You will be asked to take premedication consisting of an oral corticosteroid such as dexamethasone, one day prior to TAXOTERE administration and to continue for one or two days after it in order to minimise certain undesirable effects which may occur after the infusion of TAXOTERE in particular allergic reactions and fluid retention (swelling of the hands, feet, legs or weight gain).

During treatment, you may be given medication to maintain the number of your blood cells.

Taking/using other medicines:

It is not advisable to use any medical treatment without telling your doctor as there may be interactions between TAXOTERE and other medicines.

Please tell your doctor or hospital pharmacist if you are taking or have recently taken any other medicine which has been prescribed for you or which you bought without a prescription.

Pregnancy and breast-feeding:

TAXOTERE must NOT be administered if you are pregnant or if you are planning to become pregnant. You must take adequate contraceptive precautions during therapy and for at least three months after TAXOTERE is no longer administered to you. If pregnancy occurs during your treatment, you must immediately inform your doctor.

You must NOT breast-feed while you are treated with TAXOTERE.

If you are thinking of becoming pregnant or breastfeeding discuss it with your doctor first.

Driving and using machines:

There is no reason why you cannot drive between courses of TAXOTERE except if you feel dizzy or are unsure of yourself.

3. HOW TO USE TAXOTERE

TAXOTERE will be administered to you by a healthcare professional.

Usual dosage

The dose will depend on your weight and your general condition. Your doctor will calculate your body surface area in square meters (m²) and will determine the dose you should receive.

Method and route of administration

TAXOTERE will be given by infusion into one of your veins. The infusion will last approximately one hour during which you will be in the hospital.

Frequency of administration

You should usually receive your infusion once every 3 weeks.

Your doctor may change the dose and frequency of dosing depending on your blood tests, your general condition and your response to tAXOTERE. In particular, please inform your doctor in case of diarrhoea, sores in the mouth, feeling of numbness or pins and needles, fever and give her/him results of your blood tests. Such information will allow her/him to decide whether a dose reduction is needed. If you have any further questions on the use of this product, ask your doctor, or hospital pharmacist.

4. POSSIBLE SIDE EFFECTS

Like all other anticancer medicines, TAXOTERE can cause side effects, although not everybody gets them.

Your doctor will discuss these with you and will explain the potential risks and benefits of your treatment.

The most commonly reported adverse reactions of TAXOTERE alone are: decrease in the number of red blood cells or white blood cells, alopecia, nausea, vomiting, sores in the mouth, diarrhea and tiredness.

The severity of adverse events of TAXOTERE may be increased when taxotere is given in combination with other chemotherapeutic agents.

During the infusion at the hospital the following allergic reactions (experienced in more than 1 person in 10) may occur:

• flushing, skin reactions, itching,
• chest tightness; difficulty in breathing,
• fever or chills,
• back pain
• low blood pressure

More severe reactions may occur.

The hospital staff will monitor your condition closely during treatment. Tell them immediately if you notice any of these effects.

Between infusions of TAXOTERE the following may occur, and the frequency may vary with the combinations of drugs that are received:

Very Common: (experienced in more than 1 in 10 patients)

• infections, decrease in the number of red (anaemia), or white blood cells (which are important in fighting infection) and platelets,
• fever: if this happens you must tell your doctor immediately
• allergic reactions as described above
• loss of appetite (anorexia)
• insomnia
• feeling of numbness or pins and needles or pain in the joints of muscles
• headache
• alteration in sense of taste
• inflammation of the eye or increased tearing of the eyes
• swelling caused by faulty lymphatic drainage
• shortness of breath
• nasal drainage; inflammation of the throat and nose; cough
• bleeding from the nose
• sores in the mouth
• stomach upsets including nausea, vomiting and diarrhea, constipation
• abdominal pain
• indigestion
• short term hair loss (in most cases normal hair growth should return)
• redness and swelling of the palms of your hands or soles of your feet which may cause your skin to peel (this may also occur on the arms, face, or body)
• change in the color of your nails, which may detach
• muscle aches and pains; back pain or bone pain
• change or absence of menstrual period
• swelling of the hands, feet, legs
• tiredness; or flu-like symptoms
• weight gain or loss

Common (experienced in less than 1 in 10 but more than 1 in 100 patients)

• oral candidiasis
• dehydration
• dizziness
• hearing impaired
• decrease in blood pressure; irregular or rapid heart beat
• heart failure
• oesophagitis
• dry mouth
• difficulty or painful swallowing
• haemorrhage
• raised liver enzymes (hence the need for regular blood tests)

Uncommon: (experienced in more than 1 in 1,000 but less than 1 in 100)

• fainting
• at the injection site, skin reactions, phlebitis (inflammation of the vein) or swelling
• inflammation of the colon, small intestine; intestinal perforation

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or hospital pharmacist.

Therapeutic indications

Breast cancer

TAXOTERE (docetaxel) in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node- positive breast cancer.

TAXOTERE (docetaxel) in combination with doxorubicin is indicated for the treatment of patients with locally advanced or metastatic breast cancer who have not previously received cytotoxic therapy for this condition.

TAXOTERE (docetaxel) monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. Previous chemotherapy should have included an anthracycline or an alkylating agent.

TAXOTERE (docetaxel) in combination with trastuzumab is indicated for the treatment of patients with metastatic breast cancer whose tumors overexpress HER2 and who previously have not received chemotherapy for metastatic disease.

TAXOTERE (docetaxel) in combination with capecitabine is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic chemotherapy. Previous therapy should have included an anthracycline.

Non-small cell lung cancer

TAXOTERE (docetaxel) is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer after failure of prior chemotherapy.

TAXOTERE (docetaxel) in combination with cisplatin is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, in patients who have not previously received chemotherapy for this condition.

Prostate cancer

TAXOTERE (docetaxel) in combination with prednisone or prednisolone is indicated for the treatment of patients with hormone refractory metastatic prostate cancer.

Gastric Adenocarcinoma

TAXOTERE (docetaxel) in combination with cisplatin and 5-fluorouracil is indicated for the treatment of patients with metastatic gastric adenocarcinoma, including adenocarcinoma of the gastroesophageal junction, who have not received prior chemotherapy for metastatic disease.

Head and neck cancer

TAXOTERE (docetaxel) in combination with cisplatin and 5-fluorouracil is indicated for the induction treatment of patients with inoperable locally advanced squamous cell carcinoma of the head and neck.

Posology and method of administration

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 physician qualified in the use of anticancer chemotherapy (see section 6.6).

Recommended dosage:

For breast, non-small cell lung, gastric, and head and neck cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can be used (see section 4.4). Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities.

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 (see section 4.4).

Docetaxel is administered as a one-hour infusion every three weeks.

Breast cancer

In the adjuvant treatment of operable node-positive breast cancer, the recommended dose of docetaxel is 75 mg/m² administered 1-hour after doxorubicin 50 mg/m² and cyclophosphamide 500 mg/m² every 3 weeks for 6 cycles (see also Dosage adjustments during treatment).

For the treatment of patients with locally advanced or metastatic breast cancer, the recommended dosage of docetaxel is 100 mg/m² in monotherapy. In first-line treatment, docetaxel 75 mg/m² is given in combination therapy with doxorubicin (50 mg/m²).

In combination with trastuzumab the recommended dose of docetaxel is 100 mg/m² every three weeks, with trastuzumab administered weekly. In the pivotal trial the initial docetaxel infusion was started the day following the first dose of trastuzumab. The subsequent docetaxel doses were administered immediately after completion of the trastuzumab infusion, if the preceding dose of trastuzumab was well tolerated. For trastuzumab dosage and administration, see summary of product characteristics.

In combination with capecitabine, the recommended dose of docetaxel is 75 mg/m² every three weeks, combined with capecitabine at 1250 mg/m² twice daily (within 30 minutes after a meal) for 2 weeks followed by 1- week rest period. For capecitabine dose calculation according to body surface area, see capecitabine summary of product characteristics.

Non-small cell lung cancer

In chemotherapy naïve patients treated for non-small cell lung cancer, the recommended dose regimen is docetaxel 75 mg/m² immediately followed by cisplatin 75 mg/m² over 30-60 minutes. For treatment after failure of prior platinum-based chemotherapy, the recommended dosage is 75 mg/m² as a single agent.

Prostate cancer

The recommended dose of docetaxel is 75 mg/m². Prednisone or prednisolone 5 mg orally twice daily is administered continuously (see section 5.1).

Gastric adenocarcinoma

The recommended dose of docetaxel is 75 mg/m² as a 1 hour infusion, followed by cisplatin 75 mg/m², as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/m² per day given as a 24-hour continuous infusion for 5 days, starting at the end of the cisplatin infusion. Treatment is repeated every three weeks. Patients must receive premedication with antiemetics and appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the risk of hematological toxicities (See also Dosage adjustments during treatment).

Head and neck cancer

For the induction treatment of inoperable locally advanced squamous cell carcinoma of the head neck (SCCHN), the recommended dose of TAXOTERE is 75 mg/m² as a 1 hour infusion followed by cisplatin 75 mg/m² over 1 hour, on day one, followed by 5-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. Patients must receive premedication with antiemetics and appropriate hydration (prior to and after cisplatin administration). Prophylactic G-CSF may be used to mitigate the risk of hematological toxicities.

For cisplatin and 5-fluorouracil dose modifications, see manufacturer's summary of product characteristic.

Dosage adjustments during treatment:

General

Docetaxel should be administered when the neutrophil count is 1,500 cells/mm³.

In patients who experienced either febrile neutropenia, neutrophil <500 cells/mm³ for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during docetaxel therapy, the dose of docetaxel should be reduced from 100 mg/m² to 75 mg/m² and/or from 75 to 60 mg/m². If the patient continues to experience these reactions at 60 mg/m², the treatment should be discontinued.

ADJUVANT THERAPY FOR BREAST CANCER

In the pivotal trial in patients who received adjuvant therapy for breast cancer and who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide prophylactic coverage (eg, day 4 to 11) in all subsequent cycles. Patients who continued to experience this reaction should remain on G-CSF and have their TAXOTERE dose reduced to 60 mg/m².

However, in clinical practice neutropenia could occur earlier. Thus the use of G-CSF should be considered function of the neutropenic risk of the patient and current recommendations. Patients who experience Grade 3 or 4 stomatitis should have their dose decreased to 60 mg/m².

In combination with cisplatin

For patients who are dosed initially at docetaxel 75 mg/m² in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is <25000 cells/mm³, or in patients who experience febrile neutropenia, or in patients with serious non-hematologic toxicities, the docetaxel dosage in subsequent cycles should be reduced to 65 mg/m². For cisplatin dosage adjustments, see manufacturer's summary of product characteristics.

In combination with capecitabine

• For capecitabine dose modifications, see capecitabine summary of product characteristics.

• For patients developing the first appearance of a Grade 2 toxicity, which persists at the time of the next TAXOTERE/ 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 TAXOTERE 55 mg/m².

• For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the TAXOTERE dose.

For trastuzumab dose modifications, see trastuzumab summary of product characteristics

In combination with cisplatin and 5-fluorouracil:

If an episode of febrile neutropenia, prolonged neutropenia or neutropenic infection occurs despite G-CSF use, the docetaxel dose should be reduced from 75 to 60 mg/m². If subsequent episodes of complicated neutropenia occur the docetaxel dose should be reduced from 60 to 45 mg/m². In case of Grade 4 thrombocytopenia the docetaxel dose should be reduced from 75 to 60 mg/m². Patients should not be retreated with subsequent cycles of docetaxel until neutrophils recover to a level > 1,500 cells/mm³ and platelets recover to a level > 100,000 cells/mm³. Discontinue treatment if these toxicities persist. (See section 4.4).

Recommended dose modifications for gastrointestinal toxicities in patients treated with TAXOTERE in combination with cisplatin and 5-fluorouracil (5-FU):

Toxicity Dosage adjustment

Diarrhea grade 3 First episode: reduce 5-FU dose by 20%.

Second episode: then reduce TAXOTERE dose by 20%.

Diarrhea grade 4 First episode: reduce TAXOTERE and 5-FU doses by 20%.

Second episode: discontinue treatment.

Stomatitis grade 3 First episode: reduce 5-FU dose by 20%.

Second episode: stop 5-FU only, at all subsequent cycles.

Third episode: reduce TAXOTERE dose by 20%.

Stomatitis grade 4 First episode: stop 5-FU only, at all subsequent cycles.

Second episode: reduce TAXOTERE dose by 20%.

For cisplatin and 5-fluorouracil dosage adjustments, see manufacturers' summary of product characteristics.

In the pivotal trial in patients who received an induction treatment with docetaxel for inoperable locally advanced squamous SCCHN and who experienced complicated neutropenia (including prolonged neutropenia, febrile neutropenia, or infection), it was recommended to use G-CSF to provide prophylactic coverage (eg, day 6-15) in all subsequent cycles.

Special populations:

Patients with hepatic impairment: Based on pharmacokinetic data with docetaxel at 100 mg/m² as single agent, patients who have both elevations of transaminase (ALT and/or AST) greater than 1.5 times the upper limit of the normal range (ULN) and alkaline phosphatase greater than 2.5 times the ULN, the recommended dose of docetaxel is 75 mg/m² (see sections 4.4 and 5.2). For those patients with serum bilirubin >ULN and/or ALT and AST >3.5 times the ULN associated with alkaline phosphatase >6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical trial excluded patients with ALT and/or AST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x UNL; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Children and adolescents: The experience in children and adolescents is limited.

Elderly: Based on a population pharmacokinetic analysis, there are no special instructions for use in the elderly.

In combination with capecitabine, for patients 60 years of age or more, a starting dose reduction of capecitabine to 75% is recommended (see capecitabine summary of product characteristics)

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Docetaxel should not be used in patients with baseline neutrophil count of <1,500 cells/mm³.

Docetaxel must not be used in pregnant or breast-feeding women.

Docetaxel should not be used in patients with severe liver impairment since there is no data available (see sections 4.2 and 4.4).

Contraindications for other medicinal products also apply, when combined with docetaxel.

Special warnings and precautions for use

For breast and non-small cell lung cancers, premedication consisting of an oral corticosteroid, such as dexamethasone 16 mg per day (e.g. 8 mg BID) for 3 days starting 1 day prior to docetaxel administration, unless contraindicated, can reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. For prostate cancer, the premedication is oral dexamethasone 8 mg, 12 hours, 3 hours and 1 hour before the docetaxel infusion (see section 4.2).

Haematology

Neutropenia is the most frequent adverse reaction of docetaxel. Neutrophil nadirs occurred at a median of 7 days but this interval may be shorter in heavily pre-treated patients. Frequent monitoring of complete blood counts should be conducted on all patients receiving docetaxel. Patients should be retreated with docetaxel when neutrophils recover to a level 1,500 cells/mm³ (see section 4.2).

In the case of severe neutropenia (<500 cells/mm³ 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 (see section 4.2).

In patients treated with docetaxel in combination with cisplatin and 5-fluorouracil (TCF), febrile neutropenia and neutropenic infection occurred at lower rates when patients received prophylactic G-CSF. Patients treated with TCF should receive prophylactic G-CSF to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TCF should be closely monitored, (see sections 4.2 and 4.8).

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 following the initiation of the infusion of docetaxel, thus facilities for the treatment of hypotension and bronchospasm should be available. 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 appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with docetaxel.

Cutaneous reactions

Localised skin erythema of the extremities (palms of the hands and soles of the feet) with oedema followed by desquamation has been observed. Severe symptoms such as eruptions followed by desquamation which lead to interruption or discontinuation of docetaxel treatment were reported (see section 4.2).

Fluid retention

Patients with severe fluid retention such as pleural effusion, pericardial effusion and ascites should be monitored closely.

Patients with liver impairment

In patients treated with docetaxel at 100 mg/m² as single agent who have serum transaminase levels (ALT and/or AST) greater than 1.5 times the ULN concurrent with serum alkaline phosphatase levels greater than 2.5 times the ULN, there is a higher risk of developing severe adverse reactions such as toxic deaths including sepsis and gastrointestinal haemorrhage which can be fatal, febrile neutropenia, infections, thrombocytopenia, stomatitis and asthenia. Therefore, the recommended dose of docetaxel in those patients with elevated liver function test (LFTs) is 75 mg/m² and LFTs should be measured at baseline and before each cycle (see section 4.2).

For patients with serum bilirubin levels >ULN and/or ALT and AST >3.5 times the ULN concurrent with serum alkaline phosphatase levels >6 times the ULN, no dose-reduction can be recommended and docetaxel should not be used unless strictly indicated.

In combination with cisplatin and 5-fluorouracil for the treatment of patients with gastric adenocarcinoma, the pivotal clinical trial excluded patients with ALT and/or AST > 1.5 × ULN associated with alkaline phosphatase > 2.5 × ULN, and bilirubin> 1 x UNL; for these patients, no dose-reductions can be recommended and docetaxel should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by docetaxel in combination in the other indications.

Patients with renal impairment

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

Nervous system

The development of severe peripheral neurotoxicity requires a reduction of dose (see section 4.2).

Cardiac toxicity

Heart failure has been observed in patients receiving TAXOTERE in combination with trastuzumab, particularly following anthracycline (doxorubicin or epirubicin)-containing chemotherapy. This may be moderate to severe and has been associated with death (see section 4.8).

When patients are candidates for treatment with TAXOTERE in combination with trastuzumab, they should undergo baseline cardiac assessment. Cardiac function should be further monitored during treatment (e.g. every three months) to help identify patients who may develop cardiac dysfunction. For more details see Summary of Product Characteristics of trastuzumab.

Others

Contraceptive measures must be taken during and for at least three months after cessation of therapy.

Additional cautions for use in adjuvant treatment of breast cancer

Complicated neutropenia

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

Gastrointestinal reactions

Symptoms such as early abdominal pain and tenderness, fever, diarrhea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly.

Congestive heart failure

Patients should be monitored for symptoms of congestive heart failure during therapy and during the follow up period.

Leukemia

In the TAXOTERE, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukemia requires haematological follow-up.

Patients with 4+ nodes

The benefit/risk ratio for TAC in patients with 4+ nodes was not defined fully at the interim analysis (see section 5.1).

Elderly

There are no data available in patients>70 years of age on TAXOTERE use in combination with doxorubicin and cyclophosphamide.

Of the 333 patients treated with TAXOTERE every three weeks in a prostate cancer study, 209 patients were 65 years of age or greater and 68 patients were older than 75 years. In patients treated with TAXOTERE every three weeks, the incidence of related nail changes occurred at a rate 10% higher in patients who were 65 years of age or greater compared to younger patients. The incidence of related fever, diarrhea, anorexia, and peripheral edema occurred at rates 10% higher in patients who were 75 years of age or greater versus less than 65 years.

Among the 300 (221 patients in the phase III part of the study and 79 patients in the phase II part) patients treated with TAXOTERE in combination with cisplatin and 5-fluorouracil in the gastric cancer study, 74 were 65 years of age or older and 4 patients were 75 years of age or older. The incidence of serious adverse events was higher in the elderly patients compared to younger patients. The incidence of the following adverse events (all grades): lethargy, stomatitis, neutropenic infection occurred at rates 10% higher in patients who were 65 years of age or older compared to younger patients. Elderly patients treated with TCF should be closely monitored.

Interaction with other medicinal products and other forms of interaction

There have been no formal clinical studies to evaluate the drug interactions of docetaxel.

In vitro studies have shown that the metabolism of docetaxel may be modified by the concomitant administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450-3A such as ciclosporine, terfenadine, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these drugs as concomitant therapy since there is a potential for a significant interaction.

Docetaxel is highly protein bound (>95%). Although the possible in vivo interaction of docetaxel with concomitantly administered medication has not been investigated formally, in vitro interactions with tightly protein-bound drugs such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of docetaxel. In addition, dexamethasone did not affect protein binding of docetaxel. Docetaxel did not influence the binding of digitoxin.

The pharmacokinetics of docetaxel, doxorubicin and cyclophosphamide were not influenced by their coadministration. Limited data from a single uncontrolled study were suggestive of an interaction between docetaxel and carboplatin. When combined to docetaxel, the clearance of carboplatin was about 50% higher than values previously reported for carboplatin monotherapy.

Docetaxel pharmacokinetics in the presence of prednisone was studied in patients with metastatic prostate cancer. Docetaxel is metabolised by CYP3A4 and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of docetaxel was observed.

Pregnancy and lactation

There is no information on the use of docetaxel in pregnant women. Docetaxel has been shown to be both embryotoxic and foetotoxic in rabbits and rats, and to reduce fertility in rats. As with other cytotoxic drugs, docetaxel may cause foetal harm when administered to pregnant women. Therefore, docetaxel must not be used during pregnancy. Women of childbearing age receiving docetaxel should be advised to avoid becoming pregnant, and to inform the treating physician immediately should this occur.

Docetaxel is a lipophilic substance but it is not known whether it is excreted in human milk. Consequently, because of the potential for adverse reactions in nursing infants, breast feeding must be discontinued for the duration of docetaxel therapy.

Effects on ability to drive and use machines

Docetaxel is unlikely to affect the ability to drive or operate machines.

Undesirable effects

The adverse reactions considered to be possibly or probably related to the administration of TAXOTERE have been obtained in:

• 1312 and 121 patients who received 100 mg/m² and 75 mg/m² of TAXOTEREas a single agent respectively

• 258 patients who received TAXOTERE in combination with doxorubicin

• 406 patients who received TAXOTERE in combination with cisplatin

• 92 patients treated with TAXOTERE in combination with trastuzumab,

• 255 patients who received TAXOTERE in combination with capecitabine,

• 332 patients who received TAXOTERE in combination with prednisone or prednisolone (clinically important treatment related adverse events are presented).

• 744 patients who received TAXOTERE in combination with doxorubicin and cyclophosphamide (clinically important treatment related adverse events are presented).

• 300 gastric adenocarcinoma patients (221 patients in the phase III part of the study and 79 patients in the phase II part) who received TAXOTERE in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).

• 174 head and neck cancer patients who received TAXOTERE in combination with cisplatin and 5-fluorouracil (clinically important treatment related adverse events are presented).

These reactions were described using the NCI Common Toxicity Criteria (grade 3 = G3; grade3-4 = G3/4; grade 4 = G4) and the COSTART terms. Frequencies are defined as: very common (> 1/10), common (> 1/100, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The most commonly reported adverse reactions of TAXOTERE alone are: neutropenia (which was reversible and not cumulative; the median day to nadir was 7 days and the median duration of severe neutropenia (<500 cells/mm³) was 7 days), anemia, alopecia, nausea, vomiting, stomatits, diarrhea and asthenia. The severity of adverse events of TAXOTERE may be increased when taxotere is given in combination with other chemotherapeutic agents.

For combination with trastuzumab, adverse events (all grades) reported in 10% are displayed. There was an increased incidence of SAEs (40% vs. 31%) and Grade 4 AEs (34% vs. 23%) in the trastuzumab combination arm compared to TAXOTERE monotherapy.

For combination with capecitabine, the most frequent treatment-related undesirable effects ( 5%) reported in a phase III trial in breast cancer patients failing anthracycline treatment are presented (see capecitabine summary of product characteristics).

The following adverse reactions are frequently observed with Taxotere:

Immune system disorders:

Hypersensitivity reactions have generally occurred within a few minutes following the start of the infusion of docetaxel and were usually mild to moderate. The most frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and drug fever or chills. Severe reactions were characterised by hypotension and/or bronchospasm or generalized rash/erythema (see section 4.4).

Nervous system disorders:

The development of severe peripheral neurotoxicity requires a reduction of dose (see sections 4.2 and 4.4). Mild to moderate neuro-sensory signs are characterised by paresthesia, dysesthesia or pain including burning. Neuro-motor events are mainly characterised by weakness.

Skin and subcutaneous tissue disorders:

Reversible cutaneous reactions have been observed and were generally considered as mild to moderate. Reactions were characterised by a rash including localised eruptions mainly on the feet and hands (including severe hand and foot syndrome), but also on the 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 lead to interruption or discontinuation of docetaxel treatment were reported (see sections 4.2 and 4.4). Severe nail disorders are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis.

General disorders and administration site conditions:

Infusion site reactions were generally mild and consisted of hyper pigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein.

Fluid retention includes events such as peripheral oedema and less frequently pleural effusion, pericardial effusion, ascites and weight gain. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more. Fluid retention is cumulative in incidence and severity (see section 4.4).

TAXOTERE 100mg/m² single agent:

Blood and Lymphatic system disorders:

Rare: bleeding episodes associated with grade 3/4 thrombocytopenia

Nervous system disorders:

Reversibility data are available among 35.3% of patients who developed neurotoxicity following TAXOTERE treatment at 100 mg/m² as single agent. The events were spontaneously reversible within 3 months.

Cardiac disorders:

Uncommon: Cardiac failure (0.5%).

Gastrointestinal disorders:

Uncommon: Oesophagitis (severe 0.4%).

Skin and subcutaneous tissue disorders:

Very rare: one case of alopecia non-reversible at the end of the study. 73% of the cutaneous reactions were reversible within 21 days.

General disorders and administration site conditions:

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). The onset of moderate and severe retention is delayed (median cumulative dose: 818.9 mg/m²) in patients with premedication compared with patients without premedication (median cumulative dose: 489.7 mg/m²); however, it has been reported in some patients during the early courses of therapy.

TAXOTERE 75mg/m² single agent:

•