Docetaxel Teva 20 mg, 80 mg Concentrate for solution for infusion

1. Breast Cancer: DOCETAXEL TEVA, in combination with doxorubicin and cyclophosphamide is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. DOCETAXEL TEVA, 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. DOCETAXEL TEVA monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer, after failure of cytotoxic therapy. DOCETAXEL TEVA, 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.

2. Non-small Cell Lung Cancer (NSCLC): DOCETAXEL TEVA, in combination with cisplatin, is indicated for the treatment of patients with unresectable, locally advanced or metastatic non-small cell lung cancer, who have not previously received chemotherapy for this condition. DOCETAXEL TEVA is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer, even after failure of platinum-based chemotherapy.

3. Ovarian Cancer: DOCETAXEL TEVA is indicated, after failure of first-line or subsequent chemotherapy, for treatment of metastatic carcinoma of the ovary.

4. Prostate Cancer: DOCETAXEL TEVA in combination with prednisone or prednisolone is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

5. Head and neck Cancer: DOCETAXEL TEVA 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.

DOCETAXEL TEVA should be administered by intravenous infusion only. Dosage: A premedication consisting of a corticosteroid (see below for prostate cancer), such as oral dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days, starting one day prior to DOCETAXEL TEVA administration, unless contra-indicated, can be used. 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 TEVA infusion. Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities. DOCETAXEL TEVA is administered as a one-hour infusion every three weeks.

1. Breast Cancer: In the adjuvant treatment of operable node-positive breast cancer, the recommended DOCETAXEL TEVA dose is 75 mg/mu00b2 administered one hour after doxorubicin 50 mg/mu00b2 and cyclophosphamide 500 mg/mu00b2 every 3 weeks for 6 cycles (see also Dosage adjustments during therapy). In first line treatment, DOCETAXEL TEVA 75 mg/mu00b2 is administered in combination therapy with doxorubicin (50 mg/mu00b2). For the second line treatment of breast cancer the recommended dosage of DOCETAXEL TEVA therapy is 100 mg/mu00b2 in monotherapy. In combination with capecitabine, the recommended dose of DOCETAXEL TEVA is 75 mg/mu00b2 every three weeks, combined with capecitabine at 1250 mg/mu00b2 orally 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 the professional information for capecitabine.

2. Non-small Cell Lung Cancer: In combination therapy (chemotherapy nau00efve patients): The recommended dosage regimen is DOCETAXEL TEVA 75 mg/mu00b2 immediately followed by cisplatin 75 mg/mu00b2 over 30 to 60 minutes. In monotherapy (for previously treated patients): The recommended dosage of DOCETAXEL TEVA therapy is 100 mg/mu00b2 as a single medicine.

3. Ovarian Cancer: The recommended dosage of DOCETAXEL TEVA therapy is 100 mg/mu00b2.

4. Prostate Cancer: The recommended dose of DOCETAXEL TEVA is 75 mg/mu00b2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously. Patients should be observed closely, especially during the first and second infusion of DOCETAXEL TEVA, because of the risk of hypersensitivity reactions.

5. Head and neck Cancer: For the induction treatment of locally advanced inoperable squamous cell carcinoma of the head and neck (SCCHN), the recommended dose of DOCETAXEL TEVA is 75 mg/mu00b2 as a 1 hour infusion followed by cisplatin 75 mg/mu00b2 over 1 hour, on day one, followed by 5-fluorouracil as a continuous infusion at 750 mg/mu00b2 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). Prophylaxis for neutropenic infections should be administered. For cisplatin and 5-fluorouracil dose modifications, see local professional information.

Dosage adjustments during treatment: General: ONLY the healthcare professional can modify the schedule of administration. DOCETAXEL TEVA should be administered when the neutrophil count is u2265 1500 cells/mmu00b3. Patients who experienced either febrile neutropenia, neutrophil count < 500 cells/mmu00b3 for more than one week, severe or cumulative cutaneous reactions or severe neurosensory signs and/or symptoms, during DOCETAXEL TEVA therapy, should have the dosage of DOCETAXEL TEVA reduced, during the subsequent cycle, from 100 mg/mu00b2 to 75 mg/mu00b2 and/or from 75 mg/mu00b2 to 60 mg/mu00b2. If the patient continues to experience these reactions at 60 mg/mu00b2, the treatment should be discontinued.

Combination therapy with DOCETAXEL TEVA for NSCLC: For patients who are dosed initially at DOCETAXEL TEVA 75 mg/mu00b2 in combination with cisplatin, and whose nadir of platelet count during the previous course of therapy is < 25000 cells/mmu00b3, or in patients who experience febrile neutropenia, or in patients with serious non-haematologic toxicities, the DOCETAXEL TEVA dosage in subsequent cycles should be reduced to 65 mg/mu00b2. For cisplatin dosage adjustments, see the professional information for this medicine.

Combination therapy with DOCETAXEL TEVA for Breast Cancer: Patients who receive adjuvant therapy for breast cancer and who experience febrile neutropenia should receive G-CSF in all subsequent cycles. Patients who continue to experience this reaction should remain on G-CSF and have their DOCETAXEL TEVA dose reduced to 60 mg/mu00b2. If G-CSF is not used, the DOCETAXEL TEVA dose should be reduced from 75 to 60 mg/mu00b2. For capecitabine dose modifications when combined with DOCETAXEL TEVA, see capecitabine manufacturersu2019 professional information.

For patients developing the first appearance of a Grade 2 toxicity which persists at the time of the next DOCETAXEL TEVA/capecitabine treatment, delay treatment until resolved to Grade 0 to 1, and resume at 100 % of the original dose. For patients developing the second appearance of Grade 2 toxicity, or the first appearance of Grade 3 toxicity, at any time during the treatment cycle, delay treatment until resolved to Grade 0 to 1, and then resume treatment with DOCETAXEL TEVA 55 mg/mu00b2. For any subsequent appearances of toxicities, or any Grade 4 toxicities, discontinue the DOCETAXEL TEVA dose.

For DOCETAXEL TEVA dose modifications due to hepatic impairment, see section 4.4 section.

Special Populations: Patients with hepatic impairment: Patients with bilirubin > ULN should generally not receive DOCETAXEL TEVA. Also, patients with AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN, should generally not receive DOCETAXEL TEVA. Elderly population: Based on a population pharmacokinetic analysis, there are no special instructions for the use in the elderly. For capecitabine, dosage reduction when combined with DOCETAXEL TEVA, see capecitabine manufacturersu2019 prescribing information.

Paediatric population: The safety and effectiveness of DOCETAXEL TEVA in children have not been established.

Hypersensitivity to docetaxel or to any of the excipients listed in section 6.1. DOCETAXEL TEVA must not be used in patients with baseline neutrophil count of < 1500 cells/mmu00b3. DOCETAXEL TEVA must not be used in patients with severe liver impairment (see sections 4.2 and 4.4). Contraindications for other medicinal products also apply, when combined with DOCETAXEL TEVA. The safe use of docetaxel in children has not been established. Pregnancy and lactation as docetaxel is teratogenic in animals.

DOCETAXEL TEVA should be administered under the supervision of a qualified healthcare professional experienced in the use of antineoplastic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. The incidence of treatment-related mortality associated with DOCETAXEL TEVA therapy is increased in patients with abnormal liver function and in patients receiving higher doses.

DOCETAXEL TEVA should generally not be given to patients with serum bilirubin levels > upper limit of normal (ULN), or to patients with AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase levels > 2.5 x ULN. Patients with elevations of bilirubin or abnormalities of transaminases concurrent with alkaline phosphatase are at increased risk for the development of grade 4 neutropenia, febrile neutropenia, infections, severe thrombocytopenia, severe stomatitis, severe skin toxicity and toxic death. Patients with isolated elevations of transaminase > 1.5 x ULN also had a higher rate of febrile neutropenia grade 4 but did not have an increased incidence of toxic death. Bilirubin, AST or ALT and alkaline phosphatase values should be obtained prior to each cycle of DOCETAXEL TEVA therapy and reviewed by the treating medical practitioner.

DOCETAXEL TEVA therapy should not be given to patients with neutrophil counts of < 1500 cells/mmu00b3. In order to monitor the occurrence of neutropenia, which may be severe and result in infection, frequent blood cell counts should be performed on all patients receiving DOCETAXEL TEVA.

Severe hypersensitivity reactions characterised by hypotension and/or bronchospasm, or generalised rash/erythema occurred in 2.2 % of patients who received the recommended 3 day dexamethasone premedication. Hypersensitivity reactions requiring discontinuation of DOCETAXEL TEVA were reported in some patients who did not receive premedication. These reactions resolved after discontinuation of the infusion and the administration of appropriate therapy. DOCETAXEL TEVA must not be given to patients who have a history of severe hypersensitivity reactions to DOCETAXEL TEVA or to other medicines formulated with polysorbate 80.

Severe fluid retention occurred in 6.5 % of patients despite use of a 3 day dexamethasone premedication regimen. It was characterised by one or more of the following events: poorly tolerated peripheral oedema, generalised oedema, pleural effusion requiring urgent drainage, dyspnoea at rest, cardiac tamponade or pronounced abdominal distension (due to ascites). The use of DOCETAXEL TEVA 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. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. During the infusion it is recommended that vital functions should be closely monitored.

Premedication consisting of an oral corticosteroid (see below for prostate), such as dexamethasone 16 mg per day (e.g. 8 mg twice daily) for 3 days, starting one day prior to DOCETAXEL TEVA administration, unless contraindicated, may reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions.

Haematology: Neutropenia is the most frequent adverse reaction of DOCETAXEL TEVA. 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 TEVA. Patients should be retreated with DOCETAXEL TEVA when neutrophils recover to a level u2265 1,500 cells/mmu00b3 (see section 4.2). In the case of severe neutropenia (< 500 cells/mmu00b3 for seven days or more) during a course of DOCETAXEL TEVA 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 TEVA 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).

In patients treated with DOCETAXEL TEVA in combination with doxorubicin and cyclophosphamide (TAC), febrile neutropenia and/or neutropenic infection occurred at lower rates when patients received primary G-CSF prophylaxis. Primary G-CSF prophylaxis should be considered in patients who receive adjuvant therapy with TAC for breast cancer to mitigate the risk of complicated neutropenia (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients receiving TAC should be closely monitored (see sections 4.2 and 4.8).

Gastrointestinal reactions: Caution is recommended for patients with neutropenia, particularly at risk for developing gastrointestinal complications. Although majority of cases occurred during the first or second cycle of docetaxel containing regimen, enterocolitis could develop at any time, and could lead to death as early as on the first day of onset. Patients should be closely monitored for early manifestations of serious gastrointestinal toxicity (see section 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 TEVA, 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 TEVA and appropriate therapy. Patients who have developed severe hypersensitivity reactions should not be re-challenged with DOCETAXEL TEVA. Patients who have previously experienced a hypersensitivity reaction to paclitaxel may be at risk to develop hypersensitivity reaction to DOCETAXEL TEVA, including more severe hypersensitivity reaction. These patients should be closely monitored during initiation of DOCETAXEL TEVA therapy.

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 leads to interruption or discontinuation of DOCETAXEL TEVA treatment were reported.

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

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

Patients with liver impairment: In patients treated with DOCETAXEL TEVA at 100 mg/mu00b2 as single medicine 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 TEVA in those patients with elevated liver function test (LFTs) is 75 mg/mu00b2 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 TEVA should not be used unless strictly indicated. No data are available in patients with hepatic impairment treated by DOCETAXEL TEVA 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 TEVA.

Nervous system: The development of severe peripheral neurotoxicity, including paraesthesia, dysaesthesia and pain, has been observed in patients and requires a reduction of dose. When symptoms persist, treatment should be stopped.

Cardiac toxicity: Ventricular dysrhythmia including ventricular tachycardia (sometimes fatal) has been reported in patients treated with DOCETAXEL TEVA in combination regimens including doxorubicin, 5-fluorouracil and/or cyclophosphamide (see section 4.8). Baseline cardiac assessment is recommended.

Eye disorders: Cystoid macular oedema (CMO) has been reported in patients treated with DOCETAXEL TEVA. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination. In case CMO is diagnosed, DOCETAXEL TEVA treatment should be discontinued, and appropriate treatment initiated (see section 4.8).

Second primary malignancies: Second primary malignancies have been reported when, DOCETAXEL TEVA was given in combination with anticancer treatments known to be associated with second primary malignancies. Second primary malignancies (including acute myeloid leukemia, myelodysplastic syndrome and non-Hodgkin lymphoma) may occur several months or years after docetaxel-containing therapy. Patients should be monitored for second primary malignancies (see section 4.8).

Others: Contraceptive measures must be taken by both men and women during treatment and for men at least 6 months after cessation of therapy (see section 4.6). The concomitant use of DOCETAXEL TEVA with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) should be avoided (see section 4.5).

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

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

Leukaemia: In the DOCETAXEL TEVA, doxorubicin and cyclophosphamide (TAC) treated patients, the risk of delayed myelodysplasia or myeloid leukaemia requires haematological follow up.

Patients with 4+ nodes: As the benefit observed in patient with 4+ nodes was not statistically significant on disease-free survival (DFS) and overall survival (OS), the positive benefit/risk ratio for TAC in patients with 4+ nodes was not fully demonstrated at the final analysis.

Elderly patients: There are limited data available in patients > 70 years of age on DOCETAXEL TEVA use in combination with doxorubicin and cyclophosphamide. 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 u2265 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.

The amount of alcohol in this medicinal product may alter the effects of other medicinal products. In-vitro studies have shown that the metabolism of DOCETAXEL TEVA 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, ketoconazole and erythromycin. As a result, caution should be exercised when treating patients with these medicinal products as concomitant therapy since there is a potential for a significant interaction. In case of combination with CYP3A4 inhibitors, the occurrence of DOCETAXEL TEVA adverse reactions may increase, as a result of reduced metabolism. If the concomitant use of a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) cannot be avoided, a close clinical surveillance is warranted and a dose-adjustment of DOCETAXEL TEVA may be suitable during the treatment with the strong CYP3A4 inhibitor (see section 4.4). In a pharmacokinetic study, the co-administration of DOCETAXEL TEVA with the strong CYP3A4 inhibitor ketoconazole leads to a significant decrease in DOCETAXEL TEVA clearance by 49 %. DOCETAXEL TEVA is metabolised by CYP3A4, and prednisone is known to induce CYP3A4. No statistically significant effect of prednisone on the pharmacokinetics of DOCETAXEL TEVA was observed in studies.

DOCETAXEL TEVA is highly protein bound (> 95 %). Although the possible in vivo interaction of DOCETAXEL TEVA with concomitantly administered medicinal product has not been investigated formally, in-vitro interactions with tightly protein-bound medicine such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of DOCETAXEL TEVA. In addition, dexamethasone did not affect protein binding of DOCETAXEL TEVA. DOCETAXEL TEVA does not influence the binding of digitoxin. The pharmacokinetics of DOCETAXEL TEVA, doxorubicin and cyclophosphamide were not influenced by their co-administration. Limited data were suggestive of an interaction between DOCETAXEL TEVA and carboplatin. When combined to DOCETAXEL TEVA, the clearance of carboplatin was about 50 % higher than values previously reported for carboplatin monotherapy.

Pregnancy: Safety on the use of DOCETAXEL TEVA in pregnant women has not been established. As with other cytotoxic medicinal products, DOCETAXEL TEVA may cause foetal harm when administered to pregnant women. Therefore, DOCETAXEL TEVA must not be used during pregnancy unless clearly indicated (see section 4.3). Women of childbearing age receiving DOCETAXEL TEVA should be advised to avoid becoming pregnant, and to inform the treating healthcare professional immediately should this occur.

Breastfeeding: DOCETAXEL TEVA 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, breastfeeding must be discontinued for the duration of DOCETAXEL TEVA therapy (see section 4.3).

Contraception in males and females: An effective method of contraception should be used during treatment.

Fertility: Contraception in males and females: DOCETAXEL TEVA has genotoxic effects and may alter male fertility (see section 5.3). Therefore, men being treated with DOCETAXEL TEVA are advised not to father a child during and up to 3 months after treatment and to seek advice on conservation of sperm prior to treatment. Due to the genotoxic potential of DOCETAXEL TEVA, women of childbearing potential should use effective contraceptive measures while being treated with DOCETAXEL TEVA for 6 months following completion of treatment.

No studies on the effects on the ability to drive and use machines have been performed. The amount of alcohol in DOCETAXEL TEVA and the side effects may impair the ability to drive or use machines (see sections 4.4 and 4.8). Therefore, patients should be warned of the potential impact of the amount of alcohol and the side effects of DOCETAXEL TEVA on the ability to drive or use machines and be advised not to drive or use machines if they experience these side effects during treatment.

Summary of the safety profile for all indications: The most commonly reported adverse reactions of DOCETAXEL TEVA alone are neutropenia anaemia, alopecia, nausea, vomiting, stomatitis, diarrhoea and asthenia. The severity of adverse events of DOCETAXEL TEVA may be increased when DOCETAXEL TEVA is given in combination with other chemotherapeutic medicine. The following adverse reactions are frequently observed with DOCETAXEL TEVA:

Immune system disorders: Hypersensitivity reactions have generally occurred within a few minutes following the start of the infusion of DOCETAXEL TEVA and were usually mild to moderate. The most frequently reported symptoms were flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and 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 paraesthesia, 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 TEVA infusion. Less frequently, severe symptoms such as eruptions followed by desquamation which rarely leads to interruption or discontinuation of DOCETAXEL TEVA 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).

List of adverse reactions: System Organ Class Frequency Undesirable effects Blood and lymphatic system disorders Frequent: Bone marrow suppression and other haematological adverse reactions include neutropenia, febrile neutropenia, thrombocytopenia, anaemia and infections. Neutropenia is reversible and not cumulative. The median time to nadir is 7 days and the median duration of severe neutropenia (< 500 cells/mmu00b3) is 7 days. Fever in absence of infection, has been reported in patients with non-small cell lung cancer. Less frequent: Bleeding episodes have occurred and were rarely associated with severe thrombocytopenia (< 50000 cells/mmu00b3).

Immune system disorders Frequent: Hypersensitivity reactions may occur, usually within a few minutes following the start of the infusion of DOCETAXEL TEVA and are mostly mild to moderate. Symptoms are flushing, rash with or without pruritus, chest tightness, back pain, dyspnoea and drug fever or chills. Severe reactions characterised by hypotension and/or bronchospasm or generalised rash/erythema, requiring therapeutic intervention, may occur. These may resolve after discontinuation of the infusion and institution of appropriate therapy.

Metabolism and nutrition disorders Less frequent: Fluid accumulation: Peripheral oedema, pleural effusion, pericardial effusion, ascites, increased capillary permeability and weight gain, have been reported. The peripheral oedema usually starts at the lower extremities and may become generalised with a weight gain of 3 kg or more after 4 cycles or a cumulative dose u2265 400 mg/mu00b2. Fluid retention is cumulative in incidence and severity. Fluid retention has not been accompanied by acute episodes of oliguria or hypotension. Fluid retention has been less frequently reported in patients receiving the recommended premedication compared with patients without premedication. Dehydration and pulmonary oedema have been reported.

Nervous system disorders Frequent: Neurosensory signs characterised by paraesthesia, dysesthesia or pain, including burning, may occur. Neuromotor events, mainly characterised by weakness, may occur. Cases of convulsion or transient loss of consciousness have been observed with DOCETAXEL TEVA administration. These reactions may appear during the infusion of DOCETAXEL TEVA.

Eye disorders Less frequent: Lacrimation, with or without conjunctivitis, individual cases of lacrimal duct obstruction resulting in excessive tearing, transient visual disturbances (flashes, flashing lights, scotomata), typically occurring during medicine infusion and in association with hypersensitivity reactions.

Cardiovascular system disorders Less frequent: Venous thromboembolic events, myocardial infarction, and hypertension have been reported. Other adverse events include left ventricular dysfunction, unstable angina, dysrhythmia, sinus tachycardia, atrial flutter or paroxysmal atrial tachycardia and hypotension.

Respiratory, thoracic and mediastinal disorders Frequent: Dyspnoea may occur and is associated with acute hypersensitivity reactions, respiratory infections and cancerous lung involvement. Less frequent: Cough and epistaxis. Acute respiratory distress syndrome, interstitial pneumonia, pulmonary fibrosis and radiation recall phenomena have been reported.

Gastrointestinal system disorders Frequent: Gastrointestinal effects, such as nausea, vomiting, diarrhoea and abdominal pain, constipation, stomatitis, oesophagitis and taste perversion. Gastrointestinal bleeding, anorexia. Occurrences of dehydration as a consequence of gastrointestinal events, gastrointestinal perforation, ischaemic colitis, colitis and neutropenic enterocolitis. Less frequent: Ileus and intestinal obstruction.

Hepatobiliary system disorders Less frequent: Increases in serum levels of AST, ALT, bilirubin and alkaline phosphatase greater than 2.5 times ULN, hepatitis.

Skin and subcutaneous tissue disorders Frequent: Reversible cutaneous reactions. The cutaneous reactions are characterised by a rash, including localised eruptions mainly on the feet and hands, but also on the arms, face or thorax, and frequently associated with pruritus. Eruptions generally occurred within one week after the DOCETAXEL TEVA infusion. Nail disorders may occur. These are characterised by hypo- or hyperpigmentation and sometimes pain and onycholysis. Less frequent: Severe symptoms, such as eruptions followed by desquamation, may lead to interruption or discontinuation of DOCETAXEL TEVA treatment. Bullous eruptions, such as erythema multiforme or Stevens-Johnson syndrome.

Musculoskeletal, connective tissue and bone disorders Frequent: Arthralgia and myalgia. General disorders and administrative site conditions Frequent: Infusion site reactions are generally mild and consist of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein. Generalised or localised pain may occur, including chest pain without any cardiac or respiratory involvement. Other side-effects include alopecia and asthenia.

There were a few reports of overdose. There is no known antidote for DOCETAXEL TEVA overdose. In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. In cases of overdose, exacerbation of adverse events may be expected. The primary anticipated complications of overdose would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken, as needed.