Taxocan 20 / 80 20 mg & 80 mg Solution for infusion

Breast cancer TAXOCAN, in combination with doxorubicin and cyclophosphamide, is indicated for the adjuvant treatment of patients with operable node-positive breast cancer. TAXOCAN, 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. TAXOCAN monotherapy is indicated for the treatment of patients with locally advanced or metastatic breast cancer after failure of cytotoxic therapy. TAXOCAN, 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 TAXOCAN is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer, even after failure of prior platinum-based chemotherapy. TAXOCAN, 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.

Ovarian cancer TAXOCAN is indicated, after failure of first-line or subsequent chemotherapy, for treatment of metastatic carcinoma of the ovary.

Prostate cancer TAXOCAN, in combination with prednisone or prednisolone, is indicated for the treatment of patients with androgen independent (hormone refractory) metastatic prostate cancer.

Head and neck cancer TAXOCAN, 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.

Gastric adenocarcinoma TAXOCAN in combination with cisplatin and 5-fluorouracil is indicated for the palliative treatment of patients with advanced gastric adenocarcinoma, including adenocarcinoma of the gastro-oesophageal junction, who have not received prior chemotherapy for advanced disease.

The use of TAXOCAN should be confined to units specialised in the administration of cytotoxic chemotherapy and it should only be administered under the supervision of a medical practitioner qualified in the use of anticancer chemotherapy. Patients should be observed closely, especially during the first and second infusion of TAXOCAN, because of the risk of hypersensitivity reactions.

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

For prostate cancer, given the concurrent use of prednisone or prednisolone, the recommended premedication regimen is oral dexamethasone 8 mg, administered 12 hours, 3 hours and 1 hour before the TAXOCAN infusion. Prophylactic G-CSF may be used to mitigate the risk of haematological toxicities.

TAXOCAN is administered as a one-hour infusion every three weeks. Care should be taken with administration of the infusion to avoid extravasation.

Breast cancer In the adjuvant treatment of operable node-positive breast cancer, the recommended dose of TAXOCAN 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 Dose adjustments during treatment, below). In first-line treatment, TAXOCAN 75 mg/mu00b2 is given in combination therapy with doxorubicin (50 mg/mu00b2). For the second-line treatment of breast cancer the recommended dosage of TAXOCAN therapy is 100 mg/mu00b2 in monotherapy. In combination with capecitabine, the recommended dose of TAXOCAN is 75 mg/mu00b2 every three weeks, combined with capecitabine at 1 250 mg/mu00b2 twice daily (within 30 minutes after a meal) for two weeks, followed by a one-week rest period. For capecitabine dose calculation according to body surface area, see capecitabine package insert.

Non-small cell lung cancer (NSCLC) In combination therapy (chemotherapy nau00efve patients): The recommended dose regimen is TAXOCAN 75 mg/mu00b2 immediately followed by cisplatin 75 mg/mu00b2 over 30 u2013 60 minutes. In monotherapy (for previously treated patients): The recommended dosage of TAXOCAN therapy is 100 mg/mu00b2 as a single medicine.

Ovarian cancer The recommended dosage of TAXOCAN therapy is 100 mg/mu00b2.

Prostate cancer The recommended dose of TAXOCAN is 75 mg/mu00b2. Prednisone or prednisolone 5 mg orally twice daily is administered continuously.

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 TAXOCAN 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, the patient should receive radiotherapy. Patients must receive premedication with anti-emetics 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 leaflet.

Gastric adenocarcinoma For gastric adenocarcinoma, the recommended dose of TAXOCAN is 75 mg/mu00b2 as a 1-hour infusion, followed by cisplatin 75 mg/mu00b2, as a 1 to 3 hour infusion (both on day 1 only), followed by 5-fluorouracil 750 mg/mu00b2 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 anti-emetics and appropriate hydration for cisplatin administration. Prophylactic G-CSF should be used to mitigate the risk of haematological toxicities (see Dosage adjustments during treatment below).

Dose adjustments during treatment General: Only the medical practitioner can modify the schedule of administration. TAXOCAN should be administered when the neutrophil count is u2265 1 500 cells/mmu00b3. In patients who experienced either febrile neutropenia, neutrophil < 500 cells/mmu00b3 for more than one week, severe or cumulative cutaneous reactions or severe peripheral neuropathy during TAXOCAN therapy, the dose of TAXOCAN should be reduced 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 TAXOCAN for NSCLC: For patients who are dosed initially at TAXOCAN 75 mg/mu00b2 in combination with cisplatin and whose nadir of platelet count during the previous course of therapy is < 25 000 cells/mmu00b3, or in patients who experience febrile neutropenia, or in patients with serious non-haematological toxicities, the TAXOCAN dosage in subsequent cycles should be reduced to 65 mg/mu00b2. For cisplatin dosage adjustments, see the respective professional information leaflet.

Combination therapy with TAXOCAN for breast cancer: Patients who received adjuvant therapy for breast cancer and who experience febrile neutropenia may benefit from receiving G-CSF in all subsequent cycles. If G-CSF is not used, the TAXOCAN dose should be reduced from 75 mg/mu00b2 to 60 mg/mu00b2. Patients who experience grade 3 or 4 stomatitis or oesophagitis should have their dose decreased to 60 mg/mu00b2 while the dose of other concomitant chemotherapy should also be reduced. TAXOCAN should be stopped and not administered again in cases of grade 4 stomatitis or oesophagitis. For capecitabine dose modifications, see capecitabine professional information leaflet. For patients developing the first appearance of a grade 2 toxicity, which persists at the time of the next TAXOCAN/capecitabine treatment, delay treatment until resolved to grade 0 u2013 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 u2013 1, then resume treatment with TAXOCAN 55 mg/mu00b2. For any subsequent appearances of toxicities, or any grade 4 toxicities, discontinue the TAXOCAN dose.

Combination therapy with TAXOCAN for gastric cancer: Patients treated with TAXOCAN in combination with cisplatin and 5-fluorouracil must receive anti-emetics 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 TAXOCAN dose should be reduced from 75 mg/mu00b2 to 60 mg/mu00b2. If subsequent episodes of complicated neutropenia occur the TAXOCAN dose should be reduced from 60 mg/mu00b2 to 45 mg/mu00b2. In case of grade 4 thrombocytopenia the TAXOCAN dose should be reduced from 75 mg/mu00b2 to 60 mg/mu00b2. Patients should not be retreated with subsequent cycles of TAXOCAN until neutrophils recover to a level > 1 500 cells/mmu00b3 and platelets recover to a level > 100 000 cells/mmu00b3. Discontinue treatment if these toxicities persist.

Recommended dose modifications for gastrointestinal toxicities in patients treated with TAXOCAN in combination with cisplatin and 5-fluorouracil (5-FU) Toxicity Dose adjustments Diarrhoea grade 3 First episode: reduce fluorouracil (5-FU) dose by 20 %. Second episode: then reduce TAXOCAN dose by 20 %. Diarrhoea grade 4 First episode: reduce TAXOCAN and fluorouracil (5-FU) doses by 20 %. Second episode: discontinue treatment. Stomatitis grade 3 First episode: reduce fluorouracil (5-FU) dose by 20 %. Second episode: stop fluorouracil (5-FU) only, at all subsequent cycles. Third episode: reduce TAXOCAN dose by 20 %. Stomatitis grade 4 First episode: stop fluorouracil (5-FU) only, at all subsequent cycles. Second episode: reduce TAXOCAN dose by 20 %. For cisplatin and fluorouracil dosage adjustments, see local professional information leaflet.

Special populations Patients with hepatic impairment: For TAXOCAN dose modifications due to hepatic impairment, see section 4.4. Patients with bilirubin > ULN should generally not receive TAXOCAN. Also, patients with AST and/or ALT > 1.5 x ULN concomitant with alkaline phosphatase > 2.5 x ULN, should generally not receive TAXOCAN (see section 4.3). Children: The safety and effectiveness of TAXOCAN in children have not been established. Elderly patients: Based on a population pharmacokinetic analysis, there are no special instructions for use in elderly patients. For capecitabine dosage reduction when combined with TAXOCAN, see capecitabine professional information leaflet.

Method of administration TAXOCAN should be administered by intravenous (IV) infusion only. For recommendations on safe handling and instructions on preparation and administration of TAXOCAN, see section 6.6.

• TAXOCAN is contraindicated in patients who have a history of hypersensitivity reactions to docetaxel or polysorbate 80 or any of the other ingredients in TAXOCAN listed in section 6.1.
• TAXOCAN should not be used in patients with baseline neutrophil count of < 1 500 cells/mmu00b3.
• Pregnancy and lactation, as TAXOCAN is teratogenic in animals (see section 4.6).
• Children, as the safe use of TAXOCAN has not been established.
• TAXOCAN should not be used in patients with severe liver impairment since there are no data available (see sections 4.4 and 4.2).
• Contraindications for other medicines also apply when combined with TAXOCAN.

TAXOCAN should be administered under the supervision of a qualified medical practitioner experienced in the use of antineoplastic medicines. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. The incidence of treatment-related mortality associated with TAXOCAN therapy is increased in patients with abnormal liver function and in patients receiving higher doses. TAXOCAN 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 transaminase 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 TAXOCAN therapy and reviewed by the treating health care practitioner. TAXOCAN therapy should not be given to patients with neutrophil counts of < 1 500 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 TAXOCAN.

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

Severe fluid retention occurred in a number 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 TAXOCAN 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 with a corticosteroid 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 TAXOCAN administration, unless contraindicated, may reduce the incidence and severity of fluid retention as well as the severity of hypersensitivity reactions. The pretreatment regimen for prostate cancer is oral dexamethasone 8 mg, administered 12 hours, 3 hours and 1 hour before the TAXOCAN regimen.

There have been no formal clinical studies to evaluate the interactions of TAXOCAN. In vitro studies have shown that the metabolism of TAXOCAN may be modified by the concomitant administration of medicines which induce, inhibit or are metabolised by (and thus may inhibit the enzyme competitively) cytochrome P450 3A, such as ciclosporin, tacrolimus, cyclophosphamide, midazolam, ketoconazole, erythromycin and troleandomycin. As a result, caution should be exercised when treating patients with these medicines as concomitant therapy, since there is a potential for a significant interaction. In combination with CYP3A4 inhibitors, the occurrence of TAXOCAN side effects 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 dose reduction of TAXOCAN may be suitable during treatment. TAXOCAN is highly protein bound (> 95 %). Although the possible in vivo interaction of TAXOCAN with concomitantly administered medication has not been investigated formally, in vitro interactions with tightly protein-bound medicines such as erythromycin, diphenhydramine, propranolol, propafenone, phenytoin, salicylate, sulfamethoxazole and sodium valproate did not affect protein binding of TAXOCAN. In addition, dexamethasone did not affect protein binding of TAXOCAN. TAXOCAN did not influence the binding of digoxin. In the doxorubicin/TAXOCAN combination, the clearance of TAXOCAN was increased.

Pregnancy and lactation are contraindicated, as TAXOCAN is teratogenic in animals (see section 4.3). There are no available data on the effect of TAXOCAN on fertility.

The amount of alcohol in TAXOCAN may impair the patientu2019s ability to drive or use machines. TAXOCAN can also cause excessive tear formation which may interfere with driving. Patients should be advised not to drive or operate machines until it is established that their ability to perform such activities is not affected.

TAXOCAN 100 mg/mu00b2 and 75 mg/mu00b2 or TAXOCAN 75 mg/mu00b2 in combination with doxorubicin and cisplatin: Infections and infestations Frequent: infections Blood and lymphatic system disorders Frequent: anaemia, neutropenia, febrile neutropenia, thrombocytopenia Less frequent: bleeding episodes, bone marrow suppression Bleeding episodes may be associated with severe thrombocytopenia (< 50 000 cells/mmu00b3). Immune system disorders Frequent: anaphylactic reactions, hypersensitivity reactions Metabolism and nutrition disorders Frequent: anorexia Nervous system disorders Frequent: neurosensory signs characterised by paraesthesia, dysaesthesia or pain including burning, neuromotor events mainly characterised by weakness Less frequent: convulsions, transient loss of consciousness Eye disorders Less frequent: lacrimal duct obstruction resulting in excessive tearing, lacrimation with or without conjunctivitis, transient visual disturbances Cardiac disorders Frequent: cardiac dysrhythmia, heart failure Less frequent: pericardial effusion, myocardial infarction Vascular disorders Frequent: hypotension Less frequent: hypertension, venous thromboembolic events Respiratory, thoracic and mediastinal disorders Less frequent: dyspnoea Gastrointestinal disorders Frequent: diarrhoea, nausea, vomiting, constipation, stomatitis. Less frequent: colitis, gastrointestinal bleeding, gastrointestinal perforation, ileus, intestinal obstruction, ischaemic colitis, neutropenic enterocolitis, abdominal pain, oesophagitis, taste perversion Hepato-biliary disorders Less frequent: hepatitis, ascites Skin and subcutaneous tissue disorders Frequent: cutaneous reaction, alopecia Less frequent: severe cutaneous reaction, nail changes, erythema multiforme, Stevens-Johnson syndrome, a rash including localised eruptions mainly on the feet and hands, but also on the arms, face or thorax and frequently associated with pruritus Musculoskeletal and connective tissue disorders Frequent: arthralgia or myalgia General disorders and administration site conditions Frequent: asthenia, fever, infusion site reactions, pain, fluid accumulation Generalised or localised pain (including chest pain without any cardiac or respiratory involvement. Infusion site reactions may consist of hyperpigmentation, inflammation, redness or dryness of the skin, phlebitis or extravasation and swelling of the vein. Investigations Frequent: increased serum level of bilirubin, increased serum levels of AST, ALT and alkaline phosphatase Less frequent: increased capillary permeability.

See section 4.8.

Symptoms of overdose In case of overdose, the patient should be kept in a specialised unit and vital functions closely monitored. There is no known antidote for TAXOCAN overdosage. The primary anticipated complications of overdosage would consist of neutropenia, mucositis, cutaneous reactions and paraesthesia.

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