ETOPOSIDE

4). Posology Adult population The recommended dose of Etoposide in adult patients is 50 to 100 mg/m2/day (etoposide equivalent) on days 1 to 5 or 100 to 120 mg/m2 on days 1, 3, and 5 every 3 to 4 weeks in combination with other drugs indicated in the disease to be treated.

4) which may have compromised bone marrow reserve. The doses after the initial dose should be adjusted if neutrophil count is below 500 cells/mm3 for more than 5 days. In addition the dose should be adjusted in case of occurrence of fever, infections, or at a thrombocyte count below 25,000 cells/mm3, which is not caused by the disease.

Follow up doses should be adjusted in case of occurrence of grade 3 or 4 toxicities or if renal creatinine clearance is below 50 ml/min. At decreased creatinine clearance of 15 to 50 ml/min a dose reduction by 25% is recommended.

Administration Precautions:

As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of etoposide. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. 6).

2). Paediatric population Hodgkin’s lymphoma; non-Hodgkin’s lymphoma; acute myeloid leukaemia Etoposide in paediatric patients has been used in the range of 75 to 150 mg/m2/day (etoposide equivalent) for 2 to 5 days in combination with other antineoplastic agents.

The treatment regimen should be chosen according to the local standard of care. Ovarian cancer; small cell lung cancer; gestational trophoblastic neoplasia; testicular cancer The safety and efficacy of Etoposide below 18 years of age have not been established.

2 but no recommendation on a posology can be made. Renal Impairment In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance. 4). 4). 9). 4). 6.

Summary of the safety profile Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. In clinical studies in which etoposide was administered as a single agent at a total dose of ≥450 mg/m2 the most frequent adverse reactions of any severity were leucopenia (91%), neutropenia (88%), anaemia (72%) thrombocytopenia (23%), asthenia (39%), nausea and/or vomiting (37%), alopecia (33%) and chills and/or fever (24%).

Tabulated summary of adverse reactions The following adverse reactions were reported from etoposide clinical studies and post-marketing experience. These adverse reactions are presented by system organ class and frequency, which is defined by the following categories: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (frequency cannot be estimated from the available data).

, somnolence, fatigue) Cardiac disorders Common myocardial infarction, arrythmia System Organ Class Frequency Adverse Reaction (MedDRA Terms) Common transient systolic hypotension following rapid intravenous administration, hypertension Vascular disorders Uncommon haemorrhage Rare pulmonary fibrosis, interstitial pneumonitisRespiratory, thoracic and mediastinal disorders Not known bronchospasm Very common abdominal pain, constipation, nausea and vomiting, anorexia Common mucositis (including stomatitis and esophagitis), diarrhoea Gastrointestinal disorders Rare dysphagia, dysgeusia Hepatobiliary disorders Very common hepatotoxicity, alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased Very common alopecia, pigmentation Common rash, urticaria, pruritus Skin and subcutaneous tissue disorders Rare stevens-Johnson syndrome, toxic epidermal necrolysis, radiation recall dermatitis Reproductive system and breast disorders Not known infertility Very common asthenia, malaise Common extravasation*****, phlebitis General disorders and administration site conditions Rare pyrexia *Including opportunistic infections like pneumocystis jirovecii pneumonia **Myelosuppression with fatal outcome has been reported ***Anaphylactic reactions can be fatal ****Seizure is occasionally associated with allergic reactions.

*****Postmarketing complications reported for extravasation included local soft tissue toxicity, swelling, pain, cellulitis, and necrosis including skin necrosis. 4) with fatal outcome has been reported following administration of etoposide.

Myelosuppression is most often dose-limiting. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Granulocyte and platelet nadirs tend to occur about 10-14 days after administration of etoposide depending on the way of administration and treatment scheme.

Nadirs tend to occur earlier with intravenous administration compared to oral administration. Leucopenia and severe leucopenia (less than 1,000 cells/mm3) were observed in 91% and 17%, respectively, for etoposide. Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm3) were seen in 23% and 9% respectively, for etoposide.

Reports of fever and infection were also very common in patients with neutropenia treated with etoposide. Bleeding has been reported.

Gastrointestinal Toxicity:

Nausea and vomiting are the major gastrointestinal toxicities of etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy.

Alopecia:

Reversible alopecia, sometimes progressing to total baldness, has been observed in up to 66% of patients treated with etoposide.

Hypotension:

Transient hypotension following rapid intravenous administration has been reported in patients treated with etoposide and has not been associated with cardiac toxicity or electrocardiographic changes. Hypotension usually responds to cessation of infusion of etoposide and/or other supportive therapy as appropriate.

When restarting the infusion, a slower administration rate should be used. No delayed hypotension has been noted.

Hypertension:

In clinical studies involving etoposide, episodes of hypertension have been reported. If clinically significant hypertension occurs in patients receiving etoposide, appropriate supportive therapy should be initiated. Hypersensitivity Anaphylactic reactions have been reported to occur during or immediately after intravenous administration of etoposide.

The role that concentration or rate of infusion plays in the development of anaphylactic reactions is uncertain. Blood pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic reactions can occur with the initial dose of etoposide.

Anaphylactic reactions, manifested by chills, tachycardia, bronchospasm, dyspnoea, diaphoresis, pyrexia, pruritus, hypertension or hypotension, syncope, nausea, and vomiting have been reported to occur in 3% of patients treated with etoposide.

Facial flushing was reported in 2% of patients and skin rashes in 3%. These reactions have usually responded promptly to the cessation of the […]

Etoposide should only be administered and monitored under the supervision of a qualified physician experienced in the use of anti-neoplastic medicinal products. In all instances where the use of etoposide is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions.

Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgment of the physician.

Reinstitution of etoposide therapy should be carried out with caution, and with adequate consideration of the further need for the drug and close attention to possible recurrence of toxicity. Myelosuppression Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy.

Fatal myelosuppression has been reported following etoposide administration. Patients being treated with etoposide 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 etoposide: platelet count, hemoglobin, white blood cell count and differential.

If radiotherapy or chemotherapy has been given prior to starting etoposide treatment, an adequate interval should be allowed to enable the bone marrow to recover. Etoposide should not be administered to patients with neutrophil counts less than 1,500 cell/mm3 or platelet counts less than 100,000 cells/mm3, unless caused by malignant disease.

Doses subsequent to initial dose should be adjusted if neutrophil count less than 500 cells/mm3 occurs for more than 5 days or is associated with fever or infection, if platelet count less than 25,000 cells/mm3 occurs, if any 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 etoposide. 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 etoposide 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 etoposide , manifested by chills, pyrexia, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal.

Treatment is symptomatic. Etoposide should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician. An increased risk for infusion-related hypersensitivity reactions was observed when in-line filters were used during etoposide administration.

In-line filters should not be used. Hypotension Etoposide 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 administration of etoposide. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration Low serum albumin Low serum albumin is associated with increased exposure to etoposide.

Therefore patients with low serum albumin may be at increased risk for etoposide-associated toxicities. 2). Haematological parameters should be measured and dose adjustments in subsequent cycles considered based on haematological toxicity and clinical effect in moderate and severe renal impaired patients.

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 drugs.

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 etoposide, an effective 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.

6). 4 mg of alcohol […]

) •Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see