CARDIOXANE

Posology Cardioxane is administered by a short intravenous infusion (15 minutes), approximately 30 minutes prior to anthracycline administration at a dose equal to 10 times the doxorubicin-equivalent dose and 10 times the epirubicin-equivalent dose.

Thus it is recommended that Cardioxane is given at a dose of 500 mg/m2 when the commonly used dosage schedule for doxorubicin of 50 mg/m2 is employed or 600 mg/m2 when the commonly used dosage schedule for epirubicin of 60 mg/m2 is employed.

Paediatric population The safety and efficacy of Cardioxane in children aged 0 to 18 years have not been established. 2. 4). e. if the anthracycline dose is reduced the dexrazoxane dose should be reduced accordingly. 6.

Summary of the safety profile Cardioxane is administered together with anthracycline chemotherapy and, consequently, the relative contributions of anthracycline and Cardioxane to the adverse reaction profile may be unclear. The most common adverse reactions are haematological and gastroenterological reactions, primarily anaemia, leukopenia, nausea, vomiting and stomatitis, as well as asthenia and alopecia.

4). Tabulated list of adverse reactions The following table includes reactions from clinical trials and from post-marketing use. Due to the spontaneous nature of post-marketing reporting, such events are listed with frequency “not known” if they were not already identified as reactions from clinical trials.

Adverse reactions are ranked under headings of frequency, the most frequent first, using the following convention: very common ( ≥ 1/10); common ( ≥ 1/100 to < 1/10); uncommon ( ≥ 1/1,000 to < 1/100); not known (cannot be estimated from the available data).

Table 1 Infections and infestations Uncommon Infection, sepsis Neoplasms benign, malignant and unspecified (including cysts and polyps) Uncommon Acute myeloid leukaemia Blood and lymphatic system disorders Very common Anaemia, leukopenia Common Neutropenia, thrombocytopenia, febrile neutropenia, granulocytopenia, febrile bone marrow aplasia, white blood cell count decreased Uncommon Eosinophil count increased, neutrophil count increased, platelet count increased, white blood cell count increased, lymphocyte count decreased, monocyte count decreased Immune system disorders Not known Anaphylactic reaction, hypersensitivity Metabolism and nutrition disorders Common Anorexia Nervous system disorders Common Paraesthesia, dizziness, headache, peripheral neuropathy Uncommon Syncope Ear and labyrinth disorders Uncommon Vertigo, ear infection Cardiac disorders Common Ejection fraction decreased, tachycardia Vascular disorders Common Phlebitis Uncommon Venous thrombosis, lymphoedema Not known Embolism Respiratory, thoracic and mediastinal disorders Common Dyspnoea, cough, pharyngitis, respiratory tract infections Not known Pulmonary embolism Gastrointestinal disorders Very common Nausea, vomiting, stomatitis Common Diarrhoea, constipation, abdominal pain, dyspepsia Uncommon Gingivitis, oral candidiasis Hepatobiliary disorders Common Transaminases increased Skin and subcutaneous tissue disorders Very common Alopecia Common Nail disorder, erythema Uncommon Cellulitis General disorders and administration site conditions Very common Asthenia Common Mucosal inflammation, pyrexia, fatigue, malaise, injection site reaction (including pain, swelling, burning sensation, erythema, pruritus, thrombosis), oedema Uncommon Thirst Clinical trial data The above table shows adverse reactions reported in clinical studies and having a reasonable possibility of a causal relationship with Cardioxane.

8). Cell counts at nadir may be lower in patients treated with dexrazoxane. Haematological monitoring is thus necessary. Leucopenia and thrombocytopenia generally reverse quickly upon cessation of treatment with Cardioxane. At higher doses of chemotherapy, where the Cardioxane dose exceeds 1000 mg/m2, myelosuppression may increase significantly.

Second primary malignancies Since dexrazoxane is a cytotoxic agent, with topoisomerase II inhibition activity, combination of dexrazoxane with chemotherapy may lead to an increased risk of second primary malignancy. Oncology patients have an increased risk of second primary malignancies, regardless of treatment.

Patients who have received cancer therapy also have an increased risk of second primary malignancy. 8). In paediatric patients, second primary malignancies, including acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), have been reported in clinical trials in both dexrazoxane and control groups.

Although second primary malignancies were numerically higher in the dexrazoxane arm, there was no statistical difference between groups. Overall, the rates of second primary malignancies in the available paediatric studies in the dexrazoxane group are similar to rates determined for relevant populations in other studies (historical data).

However, the long term effect of dexrazoxane on second primary malignancies is not known and cannot be estimated from the available data. g. 8). Interference with chemotherapy Since both dexrazoxane and anthracyclines are topoisomerase inhibitors, it has been suggested that dexrazoxane may interfere with the anti-tumour efficacy of anthracyclines based on mechanism of action.

However, in most adult studies no significant difference has been identified in response rate and overall survival between dexrazoxane and control groups. A significant decrease in tumour response rate was reported in one study of advanced breast cancer patients treated with doxorubicin and dexrazoxane compared to patients treated with doxorubicin and placebo.

8). 5)