Loxat 30,0 mg/10,0 mg/300,0 mg Concentrate solution for infusion

LOXAT 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 of combination chemotherapy or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.
• Palliative treatment of advanced non-small cell lung cancer in patients who are not candidates for potentially curative surgery and/or radiation therapy.

Posology

Primary treatment of ovarian carcinoma: A combination regimen consisting of LOXAT 135 mg/m2 administered over 24 hours, followed by cisplatin 75 mg/m2, every 3 weeks. LOXAT should be administered before cisplatin.

Secondary treatment of ovarian and breast carcinoma: LOXAT 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.

Palliative treatment of advanced non-small cell lung carcinoma: The recommended dose of LOXAT is 175 mg/m2 administered over a period of 3 hours; followed by a platinum compound, with a 3 week interval between courses. LOXAT 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 haematologic toxicity increases with an increase in dose. All patients should be pre-medicated with corticosteroids, antihistamines, and H2 antagonists prior to LOXAT administration, e.g. dexamethasone 20 mg orally approximately 12 and 6 hours before LOXAT, promethazine 25 mg IV 30 to 60 minutes prior to LOXAT, and cimetidine 300 mg or ranitidine 50 mg IV 30 to 60 minutes before LOXAT. LOXAT should be administered through an in-line filter with a microporous membrane not greater than 0,22 u03bcm.

Special Populations

Hepatic impairment: See section 4.4. Dosage adjustment is recommended as shown below:

(a) Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design. {b) Dosage recommendations are for the first course of therapy: further dose reduction in subsequent courses should be based on individual tolerance. ULN = upper limit of normal

Paediatric population: The safety and efficacy of LOXAT in children has not been established (see section 4.4).

Method of administration: Intravenous use only. Information on instructions for preparation, dilution, disposal and other handling, see section 6.6.

LOXAT is contra-indicated in patients who have a history of severe hypersensitivity reactions to LOXAT, paclitaxel or other medicines formulated with poly-oxy-ethylated castor oil or to any of the excipients listed in section 6.1.

LOXAT should not be used in patients with baseline neutrophils of < 1 500/mm3. Pregnancy and lactation (see section 4.6). The safety and effectiveness of LOXAT in children have not been established.

LOXAT should be administered under the supervision of a medical practitioner experienced in the use of cancer chemotherapeutic medicines. Since severe hypersensitivity reactions may occur, appropriate supportive equipment should be available. LOXAT should be administered as a diluted infusion. LOXAT should be given before cisplatin when used in combination. Patients should be pre-treated with corticosteroids, antihistaminics and H2-antagonists before receiving LOXAT.

Severe hypersensitivity reactions: Anaphylaxis and severe hypersensitivity reactions probably histamine-mediated, characterized by dyspnoea, flushing, chest pain and tachycardia and hypotension requiring treatment, angioedema and generalized urticaria have occurred in patients receiving LOXAT. Patients with a history of severe hypersensitivity reactions to products containing Cremophor EL (e.g. ciclosporin for injection concentrate and teniposide for injection concentrate) should not be treated with LOXAT. In order to avoid the occurrence of severe hypersensitivity reactions, all patients treated with LOXAT should be premedicated with corticosteroids (such as dexamethasone), promethazine and H2 antagonists (such as cimetidine or ranitidine).

Rare fatal reactions have occurred in patients despite pre-treatment. In cases of severe hypersensitivity reactions, LOXAT infusion should be immediately discontinued, symptomatic therapy should be initiated and the patient should not be re-challenged with the medicine. Minor hypersensitivity reactions such as flushing and rash do not require interruption of therapy.

Bone marrow suppression: Bone marrow suppression (primary neutropenia) is the principal dose-limiting toxicity. Frequent monitoring of blood counts should be instituted during LOXAT treatment. Patients should not be re-treated until neutrophils recover to a level >1 500/mm3 and platelets recover to a level >100 000/mm3. In the case of severe neutropenia (< 500 cells/mm3 for seven days or more) during a course of LOXAT therapy, a 20 % reduction in dose for subsequent courses of therapy is recommended. The incidence of neurotoxicity and the severity of neutropenia increase with dose within a regimen.

Cardiovascular: Severe cardiac conduction abnormalities have been reported. If patients develop significant conduction abnormalities during LOXAT administration, appropriate therapy should be administered and continuous cardiac monitoring should be performed during subsequent therapy with LOXAT. Severe cardiovascular events were observed more frequently in patients with non-small cell lung carcinoma than breast or ovarian carcinoma.

Hypotension, hypertension and bradycardia have been observed during administration of LOXAT but generally do not require treatment. In severe cases, LOXAT infusions may need to be interrupted or discontinued at the discretion of the treating medical practitioner. Frequent vital sign monitoring, particularly during the first hour of LOXAT infusion, is recommended. Continuous cardiac monitoring is not required except for patients with serious conduction abnormalities. Cases of myocardial infarction have been reported. Congestive heart failure has been reported typically in patients who have received other chemotherapy, notably anthracyclines. Patients may experience severe cardiovascular events possibly related to LOXAT administration and include: hypertension, venous thrombosis, ventricular tachycardia, and atrioventricular conduction block. ECG alterations are experienced by some patients. The most frequently reported are non-specific repolarisation abnormalities, sinus tachycardia and premature beats. The relationship between LOXAT administration and ECG alterations is not clear.

Neurologic: Neurologic symptoms may occur following the first course and the frequency of symptoms may increase with increasing exposure to LOXAT. Sensory symptoms have usually improved or resolved within several months of LOXAT discontinuation. Pre-existing neuropathies resulting from prior therapies are not a contraindication for LOXAT therapy. Although the occurrence of peripheral neuropathy is frequent, the development of moderate to severe symptomatology is unusual and requires a dose reduction of 20 % for all subsequent courses of LOXAT.

In non-small cell lung carcinoma patients, the administration of LOXAT in combination with cisplatin resulted in greater incidence of neurotoxicity than usually seen in patients receiving single-agent LOXAT.

Hepatic: Patients with hepatic impairment may be at increased risk of toxicity particularly grade III-IV myelosuppression. Dose adjustment is recommended (see section 4.2). There is no evidence that the toxicity of LOXAT is increased when given as a 3-hour infusion in patients with mildly abnormal liver function. No data are available for patients with severe baseline cholestasis. When LOXAT is given as a 24-hour infusion to patients with moderate to severe hepatic impairment, increased myelosuppression may be seen as compared to patients with mildly elevated liver function tests given 24-hour infusions. Patients should be monitored closely for the development of profound myelosuppression. Hepatic necrosis and hepatic encephalopathy leading to death have been reported.

Injection site reaction: A specific treatment for extravasation reactions is unknown. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during administration.

Cisplatin: The recommended regimen of LOXAT administration for the primary treatment of ovarian carcinoma is for LOXAT to be given before cisplatin. When LOXAT is given before cisplatin, the safety profile of LOXAT is consistent with that reported for single agent use. When LOXAT is given after cisplatin, patients showed a more profound myelosuppression and an approximately 20 % decrease in paclitaxel clearance.

Ketoconazole: Medicines concomitantly administered with LOXAT (e.g., corticosteroids, antihistamines, and H2 antagonists) did not appear to interact adversely; however, possible interactions of LOXAT with concomitantly administered medications have not been formally investigated. Based on in vitro data, there is the possibility of an inhibition of LOXAT metabolism in patients treated with ketoconazole. As a result, caution should be exercised when treating patients with LOXAT when they are receiving ketoconazole as concomitant therapy.

Doxorubicin: Plasma levels of doxorubicin and doxorubicinol may be increased when paclitaxel and doxorubicin are used in combination. Sequence effects characterised by more profound neutropenic and stomatitis episodes, have been observed with combination use of LOXAT and doxorubicin, when LOXAT was administered before doxorubicin and using longer than recommended infusion times.

Active substances metabolised in the liver: The metabolism of paclitaxel is catalysed by cytochrome P450 isoenzymes CYP2C8 and CYP3A4, caution should be exercised when administering LOXAT concomitantly with known substrates or inhibitors of these isoenzymes (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of LOXAT may be increased due to higher paclitaxel exposure. Administering LOXAT 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.

PVC equipment: Contact of the undiluted concentrate with plasticized polyvinyl chloride (PVC) equipment or devices used to prepare solutions for infusion is not recommended. In order to minimise patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted LOXAT solution should preferably be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets. LOXAT should be administered through an in-line filter with a microporous membrane not greater than 0,22 microns. Use of filter devices such as IVEX-2 filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

Women of childbearing age/contraception in men and women: Women of childbearing potential should be advised to avoid becoming pregnant during therapy with LOXAT 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 LOXAT.

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

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

Fertility: LOXAT 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 LOXAT because of the possibility of infertility.

LOXAT contains alcohol which may impair the ability to drive or operate machines. Consideration should be given to possible CNS and other effects of alcohol.

a. Summary of the safety profile

The frequency and severity of adverse events are generally similar between patients receiving LOXAT for the treatment of ovarian, breast or lung carcinoma. None of the observed toxicities were clearly influenced by age. Safety of the LOXAT/platinum combination has been evaluated in a randomized trial in ovarian carcinoma and 2 phase III trials in non-small cell lung carcinoma. Unless otherwise mentioned the combination of LOXAT with platinum agents did not result in clinically relevant changes to the safety profile of single agent LOXAT. Bone marrow suppressions and peripheral neuropathy are the principal dose-related adverse effects associated with LOXAT. Myelosuppression is less frequent and less severe with a 3-hour infusion than with a 24-hour infusion schedule. The recommended LOXAT/cisplatin regimen for the primary treatment of ovarian cancer caused more severe myelosuppression than single dose LOXAT using the recommended schedule of 175 mg/m2 over 3-hour infusion. There was no increase in clinical sequelae, however.

b. Tabulated list of adverse reactions

There is no antidote for LOXAT overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, peripheral neurotoxicity and mucositis. Treatment is symptomatic and supportive.