Etopodal® should only be administered under the supervision of a qualified physician experienced in the use of anti-neoplastic medicinal products. In all instances where the use of Etopodal® is considered for chemotherapy, the physician must evaluate the need and usefulness of the medicinal product against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the medicinal product should be reduced in dose or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of Etopodal® therapy should be carried out with caution, and with adequate consideration of the further need for the medicinal product and close attention to possible recurrence of toxicity.
Myelosuppression
Dose-limiting bone marrow suppression is the most significant toxicity associated with Etopodal® therapy. Fatal myelosuppression has been reported following Etopodal® administration. Patients being treated with Etopodal® must be observed for myelosuppression carefully and frequently both during and after therapy.
The following haematological parameters should be measured at the start of therapy and prior to each subsequent dose of Etopodal®: platelet count, haemoglobin, white blood cell count and differential. If radiotherapy or chemotherapy has been given prior to starting Etopodal® treatment, an adequate interval should be allowed to enable the bone marrow to recover. Etopodal® should not be administered to patients with neutrophil counts below 1,500 cells/mm3 or platelet counts below 100,000 cells/mm3, unless caused by malignant disease.
Doses subsequent to the initial dose should be adjusted if neutrophil count below 500 cells/mm3 occurs for more than 5 days or is associated with fever or infection, if platelet count below 25,000 cells/mm3 occurs, if any other grade 3 or 4 toxicity develops or if renal clearance is less than 50 ml/min.
Severe myelosuppression with resulting infection or haemorrhage may occur. Bacterial infections should be brought under control before treatment with Etopodal®.
Secondary leukaemia
The occurrence of acute leukaemia, which can occur with or without myelodysplastic syndrome, has been described in patients that were treated with etoposide-containing chemotherapeutic regimens.
Neither the cumulative risk, nor the predisposing factors related to the development of secondary leukaemia are known. The roles of both administration schedules and cumulative doses of Etopodal® have been suggested, but have not been clearly defined.
An 11q23 chromosome abnormality has been observed in some cases of secondary leukaemia in patients who have received epipodophyllotoxins. This abnormality has also been seen in patients developing secondary leukaemia after being treated with chemotherapy regimens not containing epipodophyllotoxins and in leukaemia occurring de novo. Another characteristic that has been associated with secondary leukaemia in patients who have received epipodophyllotoxins appears to be a short latency period, with average median time to development of leukaemia being approximately 32 months.
Hypersensitivity
Physicians should be aware of the possible occurrence of an anaphylactic reaction with Etopodal®, manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic. Etopodal® should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
Hypotension
Etopodal® should be given only by slow intravenous infusion (usually over a 30 to 60 minute period) since hypotension has been reported as a possible side effect of rapid intravenous injection.
Injection site reaction
Injection site reactions may occur during the administration of Etopodal®. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during administration of the medicinal product.
Low serum albumin
Low serum albumin is associated with increased exposure to Etopodal®. Therefore patients with low serum albumin may be at increased risk for Etopodal®-associated toxicities.
Impaired renal function
In patients with moderate (CrCl = 15 to 50 ml/min), or severe (CrCl < 15 ml/min) renal impairment undergoing haemodialysis, Etopodal® should be administered at a reduced dose. Haematological parameters should be measured and dose adjustments in subsequent cycles considered based on haematological toxicity and clinical effect in patients with moderate and severe renal impairment.
Impaired hepatic function
Patients with impaired hepatic function should regularly have their hepatic function monitored due to the risk of accumulation.
Tumour lysis syndrome
Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic medicinal products. Close monitoring of patients is needed to detect early signs of tumour lysis syndrome, especially in patients with risk factors such as bulky treatment-sensitive tumours and renal insufficiency. Appropriate preventive measures should also be considered in patients at risk of this complication of therapy.
Mutagenic potential
Given the mutagenic potential of Etopodal®, an effective method of contraception is required for both male and female patients during treatment and up to 6 months after ending treatment. Genetic consultation is recommended if the patient wishes to have children after ending the treatment. As Etopodal® may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.
Paediatric population
The clinician should be aware that Etopodal® contains ethanol and polysorbate 80 as excipients.
Excipients
This medicinal product contains ethanol (alcohol. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breastfeeding women, children and high-risk groups such as patients with liver disease, or epilepsy.
Consideration should be given to possible effects on the central nervous system.
The amount of alcohol in this medicinal product may alter the effects of other medicinal products.
The amount of alcohol in this medicinal product may impair the patient’s ability to drive or use machines.
Etoposide injection contains polysorbate 80. In premature infants a life threatening syndrome of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable vitamin E product containing polysorbate 80.
