Palicitexal Auro 30 mg/5 ml/100 mg/67 ml/150 mg/25 ml/300 mg/50

PACLITAXEL AURO is indicated for:

• The palliative treatment of stage 3 or 4 advanced local carcinoma of the ovary after surgical resection, in combination with cisplatin.
• The palliative management of metastatic carcinoma of the ovary after failure of first line or subsequent chemotherapy.
• The treatment of metastatic carcinoma of the breast after failure combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contra-indicated.
• First line therapy of advanced or metastatic breast cancer in combination with trastuzumab in patients who over-express HER-2 at a 2+ or 3+ level as determined by immunohistochemistry.
• Palliative treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

Posology

Indication 1: Primary treatment of ovarian carcinoma: A combination regimen consisting of PACLITAXEL AURO 175 mg/m2 administered intravenously over 3 hours, followed by cisplatin 75 mg/m2 given every 3 weeks. Alternatively a combination regimen consisting of PACLITAXEL AURO 135 mg/m2 administered over 24 hours, followed by cisplatin 75 mg/m2, every 3 weeks. PACLITAXEL AURO should be administered before cisplatin.

Indication 2 and 3: Secondary treatment of ovarian carcinoma: PACLITAXEL AURO at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective in patients with metastatic carcinoma of the ovary or breast after the failure of first line or subsequent chemotherapy.

Indication 4: Combination, first-line therapy of advanced or metastatic breast cancer: In combination with trastuzumab, the recommended dose of PACLITAXEL AURO is 175 mg/m2 administered intravenously over a period of 3 hours, with a 3 week interval between courses. PACLITAXEL AURO infusion may be started the day following the first dose of trastuzumab or immediately after the subsequent dose of trastuzumab if the preceding dose of trastuzumab was well tolerated.

Indication 5: Palliative treatment of advanced non-small cell lung carcinoma: the recommended dose of PACLITAXEL AURO is 175 mg/m2 administered over a period of 3 hours; followed by a platinum compound, with a 3 week interval between courses. PACLITAXEL AURO should not be re-administered until the neutrophil count is at least 1 500/mm3 and the platelet count is at least 100 000/mm3.

Patients who experience severe neutropenia (neutrophil count <500/mm3) or moderate to severe peripheral neuropathy should receive a dose reduction of 20 % for subsequent courses (see section 4.4). The incidence and severity of neurotoxicity and haematological toxicity increases with dose. All patients must be premedicated prior to PACLITAXEL AURO administration to reduce the risk of severe hypersensitivity reactions. Such premedications may be corticosteroids, antihistamines, and H2 antagonists prior to PACLITAXEL AURO administration, e.g. dexamethasone 20 mg orally approximately 12 and 6 hours before PACLITAXEL AURO or 20 mg IV approximately 30-60 minutes prior to PACLITAXEL AURO, and cimetidine 300 mg or ranitidine 50 mg, IV 30 to 60 minutes before PACLITAXEL AURO. PACLITAXEL AURO should be administered through an in-line filter with a microporous membrane not greater than 0,22 u03bcm.

• Should not be administered to patients that have had severe hypersensitivity reactions to paclitaxel or other medicines formulated in Cremophor EL (polyoxyethylated castor oil), or to any of the excipients of PACLITAXEL AURO (see section 6.1).
• Should not be used in patients with severe baseline neutropenia (< 1500 cells/mm3).
• Safety in pregnancy and lactation has not been established. (see section 4.6)
• Safety in children has not been established.
• Liver impairment. Since PACLITAXEL AURO is partially metabolised in the liver, treatment of patients with severe hepatic conditions should be approached with added precaution. (see section 4.4).

Paclitaxel therapy must be overseen by a qualified medical practitioner with experience in the utilisation of cancer chemotherapy medicines. Since significant hypersensitivity reactions may occur, appropriate supportive equipment should be available. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during medicines administration. Patients must be pretreated with corticosteroids, antihistamines and H2 antagonists (section 4.2). Paclitaxel should be given before cisplatin when used in combination (section 4.5).

Hypersensitivity: Severe hypersensitivity characterised by dyspnoea and hypotension requiring treatment, angioedema, and generalised urticaria have occurred in patients receiving paclitaxel after adequate premedication. Fatal hypersensitivity reactions have occurred in patients despite premedication. These reactions are probably histamine mediated. In the case of severe hypersensitivity reactions, paclitaxel infusion should be discontinued immediately, symptomatic therapy should be initiated, and the patient should not be challenged with paclitaxel.

Haematology: Bone marrow suppression, primarily neutropenia, is the dose-limiting toxicity. Neutrophil nadirs occurred at a median of 11 days. Frequent monitoring of blood counts should be instituted. Patients should not be retreated until the neutrophil count is u22651.5 x 109/l and the platelets recover to u2265100 x 109 9 /l).

Cardiovascular: Severe cardiac conduction abnormalities have been reported rarely with single medicine paclitaxel. If patients develop significant conduction abnormalities during paclitaxel administration, appropriate therapy should be administered, and continuous cardiac monitoring should be performed during subsequent therapy with paclitaxel.

Hypotension, hypertension, and bradycardia have been observed during paclitaxel administration; patients are usually asymptomatic and generally do not require treatment. Frequent vital signs monitoring, particularly during the first hour of paclitaxel infusion, is recommended. Severe cardiovascular events were observed more frequently in patients with non-small cell lung cancer than in those with breast or ovarian carcinoma. ECG alterations are experienced by some patients. The most frequently reported ECG modification is non-specific repolarization abnormalities, sinus tachycardia and premature beats. The relationship between paclitaxel administration and ECG alterations is not clear.

Neurological: Peripheral neuropathy: The occurrence of peripheral neuropathy is frequent; the development of severe symptoms is rare. In severe cases, a dose reduction of 20% is recommended for all subsequent courses of paclitaxel.

Hepatic: Impaired hepatic function: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III-IV myelosuppression. There is no evidence that the toxicity of paclitaxel is increased when given as a 3-hour infusion to patients with mildly abnormal liver function. No data are available for patients with severe baseline cholestasis. When paclitaxel is given as a longer infusion, increased myelosuppression may be seen in patients with moderate to severe hepatic impairment. Patients should be monitored closely for the development of profound myelosuppression (see section 4.2). Hepatic necrosis and hepatic encephalopathy leading to death have been reported. Elevations in alkaline phosphatase and AST (SGOT) have been reported. Inadequate data are available to recommend dosage alterations in patients with mild to moderate hepatic impairments (see section 5.2). Patients with severe hepatic impairment must not be treated with paclitaxel.

Paclitaxel clearance is not affected by cimetidine premedication. Cisplatin: Paclitaxel is recommended to be administered before cisplatin. When given before cisplatin, the safety profile of paclitaxel is consistent with that reported for single agent use. Administration of paclitaxel after cisplatin treatment leads to greater myelosuppression and about a 20% decrease in paclitaxel clearance. Patients treated with paclitaxel and cisplatin may have an increased risk of renal failure as compared to cisplatin alone in gynaecological cancers.

Doxorubicin: Since the elimination of doxorubicin and its active metabolites can be reduced when paclitaxel and doxorubicin are given closer in time, paclitaxel for initial treatment of metastatic breast cancer should be administered 24 hours after doxorubicin (see section 5.2). Sequence effects characterised by more profound neutropenic and stomatitis episodes have been observed with combination use of paclitaxel and doxorubicin when paclitaxel was administered before doxorubicin and using longer than recommended infusion times (paclitaxel administered over 24 hours; doxorubicin over 48 hours).

Active substances metabolised in the liver: The metabolism of paclitaxel is catalysed, in part, by cytochrome P450 isoenzymes CYP2C8 and CYP3A4. Therefore, in the absence of a Pharmacokinetics drug-drug interaction study, caution should be exercised when administering paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g.ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised because of lower paclitaxel exposures.

Women of childbearing potential should be advised to avoid becoming pregnant during therapy with PACLITAXEL AURO and to inform the treating medical practitioner immediately should this occur. Female and male patients of fertile age, and/or their partners should use contraception for at least 6 months after treatment with paclitaxel.

Pregnancy: PACLITAXEL AURO should not be used during pregnancy. There is no information on the use of PACLITAXEL AURO in pregnant women. PACLITAXEL AURO may cause foetal harm when administered to pregnant women.

Breastfeeding: It is not known whether PACLITAXEL AURO is excreted in human milk. Breast feeding should be discontinued for the duration of PACLITAXEL AURO therapy.

Fertility: PACLITAXEL AURO has been shown to be embryotoxic, foetotoxic and to decrease fertility in animal studies. Male patients should seek advice regarding cryo-conservation of sperm prior to treatment with paclitaxel because of the possibility of infertility.

This medicinal product contains alcohol. It may also lead to eye disorders, which may impair the ability to drive or operate machines. In addition, some side effects such as hypotension and eye disorders may impair ability to drive.

a) Summary of adverse effects

The frequency and severity of adverse events are generally similar between patients receiving PACLITAXEL AURO for the treatment of ovarian, breast or lung carcinoma. None of the observed toxicities were clearly influenced by age.

b) Tabulated list of adverse reactions

The table below lists undesirable effects regardless of severity associated with the administration of single agent paclitaxel administered as a three-hour infusion in the metastatic setting (812 patients treated in clinical studies) and as reported in the post-marketing surveillance of paclitaxel.

Symptoms: See side effects. Complications resulting from PACLITAXEL AURO overdosage may result in bone marrow suppression, peripheral neurotoxicity, and mucositis.

Treatment: There is no known curative measure for excessive doses (antidote). Treatment is symptomatic and supportive. Overdoses in paediatric patients may be associated with acute ethanol toxicity.