Etoposide 100 Mg/5 Ml Solution

Testicular tumours u2013 first line ETOPOSIDE FRESENIUS 20 mg/mL intravenous injection is indicated in combination with other approved chemotherapeutic medicines. Refractory testicular tumours In combination with other approved medicines, for those with refractory testicular tumours who have already received appropriate surgical, chemotherapeutic and radiotherapeutic treatment. Small cell anaplastic lung tumours ETOPOSIDE FRESENIUS 20 mg/mL injection is indicated in combination with other approved chemotherapeutic medicines for the treatment of small cell anaplastic lung tumours. Malignant (non-Hodgkin's) lymphomas ETOPOSIDE FRESENIUS 20 mg/mL injection is indicated for the treatment of malignant (non-Hodgkin's) lymphoma, especially of the histiocytic (large cell diffuse) variety in combination with other approved chemotherapeutic medicines.

Safety and efficacy in paediatric patients have not been established. ETOPOSIDE FRESENIUS 20 mg/mL injection should only be administered and monitored under the supervision of a qualified medical practitioner experienced in the use of antineoplastic medicines (see section 4.4).

Posology Adult population The recommended intravenous dose of ETOPOSIDE FRESENIUS 20 mg/mL in adult patients is 50 to 100 mg/m2 per day 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 approved relevant medicines. Dosage should be adjusted according to the individual requirements of each patient, based on clinical response and the appearance or severity of toxicity. The dosage may also need to be adjusted if the patient has received radiation or other chemotherapy. Renal impairment In patients with renal impairment the following initial dose adjustment should be considered based on measured creatinine clearance: Measured creatinine clearance > 50 mL/min * 15-50 mL/min Dose of ETOPOSIDE FRESENIUS 20 mg/mL 100 % of dose 75 % of dose * data not available for creatinine clearance < 15 mL/min and further dose reduction should be considered.

Method of administration Administration precautions: Caution should be exercised in the handling and preparation of ETOPOSIDE FRESENIUS 20 mg/mL. Skin reactions associated with unintentional exposure to ETOPOSIDE FRESENIUS 20 mg/mL may occur. The use of gloves and masks is recommended. If ETOPOSIDE FRESENIUS 20 mg/mL Injection comes into contact with skin or mucosa, immediately wash the skin with soap and water and flush the mucosa with water (see section 6.6).

Hypotension following rapid intravenous infusion of ETOPOSIDE FRESENIUS 20 mg/mL has been reported. It is recommended that ETOPOSIDE FRESENIUS 20 mg/mL is administered by slow intravenous infusion (usually over a 30 to 60 minute period) (see section 4.4 and 6.6). Hypotension usually responds when the infusion is stopped and/or other supportive therapy as appropriate. When restarting the infusion, a slower rate of administration should be used. During intravenous infusion, great care must be taken to ensure that the catheter stays in the vein, as any leakage into surrounding tissue is highly irritant. ETOPOSIDE FRESENIUS 20 mg/mL should not be administered intra-arterially, intra-pleurally or intra-peritoneally. ETOPOSIDE FRESENIUS 20 mg/mL SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS PUSH. For instructions on dilution of ETOPOSIDE FRESENIUS 20 mg/mL before administration, see section 6.6.

• Hypersensitivity to etoposide or to any of the excipients of ETOPOSIDE FRESENIUS 20 mg/mL, listed in section 6.1.
• Concomitant use of yellow fever vaccine or other live vaccines is contraindicated in immunosuppressed patients (see section 4.5).
• Severe hepatic dysfunction.
• Severely impaired medullary haematopoiesis (particularly after extensive radio- and/or chemotherapy or secondary to neoplastic infiltration). This may be evidenced by mild to marked leukopenia and/or thrombocytopenia.
• Renal function impairment.
• Chickenpox, existing or recent (including recent exposure).
• Herpes zoster.
• Bone marrow depression.
• Pregnancy and lactation (see section 4.6).

ETOPOSIDE FRESENIUS 20 mg/mL should only be administered and monitored under the supervision of a qualified medical practitioner experienced in the use of antineoplastic medicines. In all instances where the use of ETOPOSIDE FRESENIUS 20 mg/mL is considered for chemotherapy, the medical practitioner should evaluate the need and usefulness of the medicine against the risk of adverse reactions. If severe reactions occur, ETOPOSIDE FRESENIUS 20 mg/mL should be reduced in dosage or discontinued, and appropriate corrective measures should be taken according to the clinical judgment of the medical practitioner. Reinstitution of ETOPOSIDE FRESENIUS 20 mg/mL therapy should be carried out with caution, and with adequate consideration of the further need for the treatment and close attention to possible recurrence of toxicity.

Injection site reaction Injection site reactions may occur during administration of ETOPOSIDE FRESENIUS 20 mg/mL. Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during administration of the medicine.

Hypersensitivity Medical practitioners should be aware of the possible occurrence of an anaphylactic reaction with ETOPOSIDE FRESENIUS 20 mg/mL, manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic.

The infusion of ETOPOSIDE FRESENIUS 20 mg/mL should be terminated immediately, followed by the administration of pressor medicines, corticosteroids, antihistamines or volume expanders at the discretion of the medical practitioner. 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.

Myelosuppression Dose-limiting bone marrow suppression is the most significant toxicity associated with ETOPOSIDE FRESENIUS 20 mg/mL therapy. Fatal myelosuppression has been reported. Patients being treated with ETOPOSIDE FRESENIUS 20 mg/mL should 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 FRESENIUS 20 mg/mL: platelet count, haemoglobin, white blood cell count and differential. If radiotherapy or chemotherapy has been given prior to starting ETOPOSIDE FRESENIUS 20 mg/mL treatment, an adequate interval should be allowed to enable the bone marrow to recover. ETOPOSIDE FRESENIUS 20 mg/mL should not be administered to patients with neutrophil counts less than 1 500 cells/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. Dosage should be modified to consider the myelosuppressive effects of other medicines in the combination or the effects of prior radiation therapy or chemotherapy which may have compromised bone marrow reserve.

Severe myelosuppression with resulting infection or haemorrhage may occur. Bacterial infections should be brought under control before treatment with ETOPOSIDE FRESENIUS 20 mg/mL.

Tumour lysis syndrome Tumour lysis syndrome (sometimes fatal) has been reported following the use of ETOPOSIDE FRESENIUS 20 mg/mL in association with other chemotherapeutic medicines. 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.

Thrombocytopenia If thrombocytopenia occurs because of administration of ETOPOSIDE FRESENIUS 20 mg/mL, patients should be observed carefully for signs of bleeding (skin, intravenous puncture sites, mucosae, unusual bruising, melaena stools, haematuria). Intramuscular injections, alcohol, aspirin and contact sports should be avoided. Platelet transfusions may be required. Patients who develop leukopenia should be carefully observed for signs of infection. Antibiotic support may be necessary. Immunisations should be avoided unless approved by the attending doctor.

Secondary leukaemia The occurrence of acute leukaemia, which can occur with or without myelodysplastic syndrome, has been described in patients treated with ETOPOSIDE FRESENIUS 20 mg/mL 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 FRESENIUS 20 mg/mL 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.

Hypotension ETOPOSIDE FRESENIUS 20 mg/mL 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.

Low serum albumin Low serum albumin is associated with increased exposure to ETOPOSIDE FRESENIUS 20 mg/mL. Therefore, patients with low serum albumin may be at increased risk for etoposide-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, ETOPOSIDE FRESENIUS 20 mg/mL should be administered at a reduced dose (see section 4.2). 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 of ETOPOSIDE FRESENIUS 20 mg/mL.

Paediatric use Safety and efficacy in paediatric patients have not been established.

Excipient (s) that the medical practitioner should be aware of: Ethanol ETOPOSIDE FRESENIUS 20 mg/mL contains 30,5 % v/v ethanol (alcohol), which corresponds to 0,305 mL (241 mg) of ethanol per ml of concentrate, i.e. up to 1,2 g ethanol per 5 mL vial. Harmful for those suffering from alcoholism. To be considered in pregnant or breastfeeding women, children and high-risk groups such as patients with liver disease, or epilepsy. Benzyl alcohol Benzyl alcohol may cause allergic reactions. This medicine contains 30 mg benzyl alcohol in each mL. Benzyl alcohol has been linked with the risk of severe side effects including breathing problems (called u201cgasping syndromeu201d) in young children. Caution should be exercised if the patient has a liver or kidney disease. This is because large amounts of benzyl alcohol can build-up in the body and may cause side effects (called u201cmetabolic acidosisu201d). ETOPOSIDE FRESENIUS 20 mg/mL is contraindicated for use in pregnancy or breastfeeding. See section 4.3 u201cContraindicationsu201d. Polysorbate 80 ETOPOSIDE FRESENIUS 20 mg/mL Injection contains polysorbate 80. In new-born infants a life-threatening syndrome of liver, cholestasis and renal failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable vitamin E product containing polysorbate 80.

Effects of other medicines on the pharmacokinetics of etoposide High dose ciclosporin, resulting in plasma concentrations above 2 000 ng/mL, administered with oral etoposide has led to an 80 % increase in etoposide exposure (AUC) with a 38 % decrease in total body clearance of etoposide in comparison with etoposide alone. Concomitant treatment with cisplatin is associated with reduced total body clearance of etoposide. Concomitant phenytoin or phenobarbital therapy is associated with increased etoposide clearance and reduced efficacy, and other enzyme-inducing antiepileptic therapy may be associated with increased etoposide clearance and reduced efficacy. In vitro, plasma protein binding is 97 %. Phenylbutazone, sodium salicylate, and acetylsalicylic acid may displace etoposide from plasma protein binding.

Effect of etoposide on the pharmacokinetics of other medicines Co-administration of antiepileptic medicines and ETOPOSIDE FRESENIUS 20 mg/mL injection can lead to decreased seizure control due to pharmacokinetic interactions between the medicines. Co-administration of warfarin and etoposide may result in elevated international normalized ratio (INR). Close monitoring of INR is recommended.

Pharmacodynamic interactions There is an increased risk of fatal systemic vaccinal disease with the use of yellow fever vaccine. Live vaccines are contraindicated in immunosuppressed patients (see section 4.3).

Prior or concurrent use of other medicines with similar myelosuppressant action as ETOPOSIDE FRESENIUS 20 mg/mL may be expected to have additive or synergetic effects (see section 4.4). Cross-resistance between anthracyclines and etoposide has been reported in preclinical experiments.

Paediatric population Interaction studies have only been performed in adults.

Safety in pregnancy and lactation has not been established (see section 4.3). Women of childbearing potential/ Contraception in males and females Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during ETOPOSIDE FRESENIUS 20 mg/mL therapy. Etoposide has been shown to be teratogenic in mice and rats. Given the mutagenic potential of ETOPOSIDE FRESENIUS 20 mg/mL, 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.

Pregnancy There are no or limited amount of data from the use of etoposide in pregnant women. Studies in animals have shown reproductive toxicity. In general etoposide can cause foetal harm when administered to pregnant women. ETOPOSIDE FRESENIUS 20 mg/mL injection should not be used during pregnancy unless the clinical condition of the woman requires treatment with ETOPOSIDE FRESENIUS 20 mg/mL. Women of childbearing potential should be advised to avoid becoming pregnant. Women of childbearing potential should be advised to use effective contraception during and up to 6 months after treatment. If ETOPOSIDE FRESENIUS 20 mg/mL is used during pregnancy, or if the patient becomes pregnant while receiving the medicine, the patient should be informed of the potential hazard (mutagenic potential) to the foetus.

Breastfeeding ETOPOSIDE FRESENIUS 20 mg/mL is excreted in human milk. There is the potential for serious adverse reactions in nursing infants from etoposide. A decision should be made whether to discontinue breastfeeding or to discontinue ETOPOSIDE FRESENIUS 20 mg/mL injection (see section 4.3).

Benzyl alcohol is probably excreted into breastmilk and can be orally absorbed by the infant (see section 4.4).

Fertility As etoposide may decrease male fertility, preservation of sperm may be considered for the purpose of future fatherhood.

No studies on the effects on the ability to drive and use machines have been performed. ETOPOSIDE FRESENIUS 20 mg/mL may cause adverse reactions that affect the ability to drive or use machines such as fatigue, somnolence, nausea, vomiting, cortical blindness, hypersensitivity reactions with hypotension. See section 4.8. Patients who experience such adverse reactions should be advised to avoid driving or using machines.

Summary of the safety profile Dose-limiting bone marrow suppression is the most significant toxicity associated with ETOPOSIDE FRESENIUS 20 mg/mL therapy. In clinical studies in which etoposide was administered as monotherapy at a total dose of u2265 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 list of adverse reactions System organ class Frequency Adverse reaction Infections and infestations Frequent opportunistic infections like pneumocystis jirovecii pneumonia 1 Neoplasms benign, malignant and unspecified (including cysts and polyps) Frequent acute leukaemia Blood and lymphatic system disorders Frequent anaemia, leukopenia, myelosuppression (including fatal outcome), neutropenia, thrombocytopenia, acute leukaemia Immune system disorders Frequent anaphylactic reactions (can be fatal) Unknown angioedema, bronchospasm Metabolism and nutrition disorders Unknown tumour lysis syndrome (sometimes fatal) Nervous system disorders Frequent dizziness 1 Ref 1 (a) Page 1, Page 4 (d)

Less frequent neuropathy peripheral, seizure (sometimes due to allergic reactions), cortical blindness transient, neurotoxicities (e.g., somnolence and fatigue), optic neuritis. Cardiac disorders Frequent dysrhythmia, myocardial infarction Vascular disorders Frequent hypertension, transient systolic hypotension following rapid intravenous administration Less frequent haemorrhage Respiratory, thoracic and mediastinal disorders Less frequent interstitial pneumonitis, pulmonary fibrosis Unknown bronchospasm Gastrointestinal disorders Frequent abdominal pain, anorexia, constipation, nausea and vomiting, diarrhoea, mucositis (including stomatitis and esophagitis) Less frequent dysgeusia, dysphagia Hepatobiliary disorders Frequent alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased, hepatotoxicity Skin and subcutaneous tissue disorders Frequent alopecia, pigmentation, pruritus, rash, urticaria Less frequent radiation recall dermatitis, Stevens-Johnsons syndrome, toxic epidermal necrolysis Reproductive system and breast disorders Unknown infertility General disorders and administration site conditions Frequent asthenia, malaise, extravasation (including local soft tissue toxicity, swelling, pain, cellulitis, and necrosis including skin necrosis), phlebitis Less frequent pyrexia

Description of selected adverse reactions In the paragraphs below the incidences of adverse events, given as the mean percent, are derived from reported studies using etoposide as monotherapy. Haematological toxicity: Myelosuppression (see section 4.4) 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.

Leukopenia and severe leukopenia (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. The reports of fever and infection were also very common in patient with neutropenia treated with etoposide. Bleeding has been reported.

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

Alopecia Reversible alopecia, sometimes progressing to total baldness was 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 injection, 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 FRESENIUS 20 mg/mL. Anaphylactic reactions (see section 4.4), manifested by chills, tachycardia, bronchospasm, dyspnoea, diaphoresis, pyrexia, pruritus, hypertension or hypotension, syncope, nausea, and vomiting have been reported to occur in 3 % (7 of 245 patients treated with etoposide in 7 clinical studies) 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 infusion and administration of pressor medicines, corticosteroids, antihistamines, or volume expanders as appropriate.

Acute fatal reactions associated with bronchospasm have been reported with etoposide. Apnoea with spontaneous resumption of breathing following cessation of infusion have also been reported.

Metabolic complications Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic medicines (see section 4.4).

Paediatric population The safety profile between paediatric patients and adults is expected to be similar.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website.

Healthcare providers are asked to report any suspected adverse drug reactions to the Holder of the Certificate of Registration at the following email address: [email protected] and to the relevant medicineu2019s regulatory authority in the country where the product is marketed.

Total doses of 2,4 u2013 3,5 g/m2 of etoposide administered intravenously over 3 days have resulted in severe mucositis and myelotoxicity. Metabolic acidosis and severe hepatic toxicity have been reported in patients receiving higher than recommended intravenous doses of ETOPOSIDE FRESENIUS 20 mg/mL. There is no specific antidote available. Treatment should therefore be symptomatic and supportive, and patients should be closely monitored. Etoposide and its metabolites are not dialyzable.