1. Name Of The Medicinal Product
Etoposide 20 mg/ml Injection
2. Qualitative And Quantitative Composition
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For excipients, see section 6.1
3. Pharmaceutical Form
Concentrate for solution for infusion.
A clear, pale to slightly yellow solution, free from visible particulates.
4. Clinical Particulars
4.1 Therapeutic Indications
Etoposide is an anti-neoplastic drug for intravenous use, which can be used alone or in combination with other oncolytic drugs. Present data indicate that etoposide is applicable in the therapy of: small cell lung cancer, non-seminomatous testicular carcinoma.
4.2 Posology And Method Of Administration
Etoposide is administered by slow intravenous infusion only. The drug should not be given by rapid intravenous injection and should be diluted before infusion.
Adults: The recommended course of Etoposide Injection is 60-120 mg/m2, IV daily for five consecutive days. As Etoposide Injection produces myelosuppression, courses may not be repeated more frequently than at 21 day intervals. Repeat courses of Etoposide Injection should not be given until the blood picture has been checked for evidence of myelosuppression and found to be satisfactory.
Immediately prior to administration, the required dose of Etoposide Injection must be diluted with 0.9% Sodium Chloride for Injection or 5% w/v Glucose Intravenous Infusion to give a solution concentration of not more than 0.25 mg/ml of etoposide; it should then be given by slow intravenous infusion over a period of not less than 30 minutes. Care should be taken to avoid extravasation.
The intravenous solution is suitable for infusion in glass or PVC containers.
Hepatic: Etoposide is contraindicated in patients with severe hepatic impairment.
Renal: In patients with impaired renal function where hepatic function is normal, the dose of etoposide should be reduced and haematological nadirs and renal function monitored.
A suggested dosage schedule based on creatinine clearance is as follows:
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4.3 Contraindications
Etoposide is contraindicated in patients with severe hepatic dysfunction or in those patients who have demonstrated hypersensitivity to the drug.
Etoposide must not be given by intra-cavitary injection.
4.4 Special Warnings And Precautions For Use
Etoposide should be administered by individuals experienced in the use of antineoplastic therapy.
When etoposide is administered intravenously care should be taken to avoid extravasation.
If radiotherapy and/or chemotherapy has been given prior to starting etoposide treatment, an adequate interval should be allowed to enable the bone marrow to recover. If the leucocyte count falls below 2,000/mm3, treatment should be suspended until the circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3 leucocytes above 4,000/mm3) with recovery about 21 days after the last dose. Peripheral blood counts and liver function should be monitored. (see adverse reactions)
Bacterial infections should be brought under control before treatment with etoposide commences.
The occurrence of acute leukaemia, which can occur with or without a pre-leukaemic phase has been reported rarely in patients treated with etoposide in association with other anti-neoplastic drugs.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Potentially hazardous interactions
No significant interactions of this type have been reported.
Potentially useful interactions
Etoposide is commonly used in association with other cytotoxic drugs and synergistic effects are thought to occur in most instances in terms of cytotoxic effect. Such synergism has been substantiated in vitro for certain drugs, including methotrexate and cisplatin.
4.6 Pregnancy And Lactation
Etoposide should not normally be administered to patients who are pregnant or to mothers who are breast feeding. Women of childbearing potential should be advised to avoid becoming pregnant. Safe use in pregnancy has not been established. Etoposide is teratogenic in rats at dose levels equivalent to those in clinical use. The influence of etoposide on human fertility has not been determined. In-vitro tests indicate that etoposide is mutagenic.
4.7 Effects On Ability To Drive And Use Machines
Adverse reactions such as fatigue and transient cortical blindness, suggest that driving or using machinery is not recommended soon after treatment with etoposide.
4.8 Undesirable Effects
Adverse effects
Haematological: The dose limiting toxicity of etoposide is myelosuppression predominantly leucopenia and thrombocytopenia. Anaemia occurs infrequently.
The leucocyte count nadir occurs approximately 21 days after treatment.
Alopecia: Alopecia occurs in approximately 66% of the patients and is reversible on cessation of therapy.
Gastrointestinal: Nausea and vomiting are the major gastrointestinal toxicities and occur in approximately 30-40% of Patients. Anti-emetics are useful in controlling these side effects. Abdominal pain, diarrhoea, anorexia, oesophagitis and stomatitis occur infrequently.
Other Toxicities
Hypotension may occur following an excessively rapid infusion and may be reversed by slowing the infusion rate.
Anaphylactoid reactions have been reported following administration of etoposide. Higher rates of anaphylactoid reactions have been reported in children who received infusions at higher concentrations than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactoid reactions is uncertain. These reactions have usually responded to cessation of therapy and administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate.
Apnoea with spontaneous resumption of breathing following discontinuation of etoposide has been reported. Sudden fatal reactions associated with bronchospasm have been reported. Hypertension and/or flushing have also been reported. Blood pressure usually returns to normal within a few hours after cessation of the infusion.
The use of etoposide has been reported infrequently to cause peripheral neuropathy.
Etoposide has been shown to reach high concentrations in the liver and kidney, thus presenting a potential for accumulation in cases of functional impairment. Somnolence, fatigue, aftertaste, fever, rash, pigmentation, pruritus, urticaria, dysphagia, transient cortical blindness and a single case of radiation recall dermatitis have also been reported following the administration of etoposide.
4.9 Overdose
No proved antidotes have been established for etoposide overdosage. Treatment should be symptomatic and supportive.
Total doses of 2.4 to 3.5 g/m2 administered i.v. over three days have resulted in severe mucositis and myelotoxicity. Metabolic acidosis and cases of severe hepatic toxicity have been reported in patients receiving higher than recommended doses of etoposide.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Etoposide is a semisynthetic podophyllotoxin derivative with significant cytotoxic activity. Etoposide interferes with the function of topoisomerase II (DNA unwinding enzyme) preventing the rejoining of DNA in the final phase of topoisomerase's action. Single and double strand DNA breaks result. Cell death is in proportion to drug concentration and exposure period. Etoposide is phase specific, with cells being arrested in S of early G2 phases of the cell cycle.
5.2 Pharmacokinetic Properties
The pharmacokinetics of etoposide are subject to considerable interindividual variation. It is rapidly distributed and is approximately 94% protein bound in human serum. Plasma decay kinetics follow a bi-exponential curve andcorrespond to a two compartmental model. The mean volume of distribution is approximately 32% of body weight. Etoposide demonstrates relatively poor penetration into the cerebrospinal fluid. Urinary excretion is approximate 45% of an administered dose, two thirds being excreted unchanged in 72 hours.
5.3 Preclinical Safety Data
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Citric acid (anhydrous)
Polysorbate 80
Macrogol 300
Ethanol (anhydrous)
6.2 Incompatibilities
Etoposide Injection should not be mixed with other antineoplastic agents in the infusion solution. Etoposide Injection should not be physically mixed with any other drug.
6.3 Shelf Life
Product as packaged for sale: 2 years
Following reconstitution: 6 hours
6.4 Special Precautions For Storage
Product as packaged for sale:Do not store above 25oC.
Following reconstitution: Chemical and physical in-use stability has been demonstrated for 6 hours at below 25oC. However, from a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and should not exceed 24 hours at 2 – 8 oC.
6.5 Nature And Contents Of Container
5 x 100 mg/5 ml, 5 x 200 mg/10 ml, 1 x 1 g/50 ml presentations in clear, Type I glass vials with stoppers.
6.6 Special Precautions For Disposal And Other Handling
Solutions of concentrations greater than 0.25 mg/ml may show signs of precipitation, and therefore not recommended.
The intravenous solution is suitable for infusion in glass or PVC containers.
Etoposide should not be physically mixed with any other drug.
Guidelines for the safe handling of antineoplastic agents:
1. Trained personnel should reconstitute the drug.
2. This should be performed in a designated area.
3. Adequate protective gloves should be worn.
4. Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or saline.
5. The cytotoxic preparation should not be handled by pregnant staff.
6. Adequate care and precautions should be taken in the disposal of items (syringes needles etc) used to reconstitute cytotoxic drugs. Excess material and body waste may be disposed of by placing in double sealed polythene bags and incinerating at a temperature of 1,000°C. Liquid waste may be flushed with copious amount of water.
7. The work surface should be covered with disposable plastic-backed absorbent paper.
8. Use Luer-Lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.
7. Marketing Authorisation Holder
Faulding Pharmaceuticals Plc
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
United Kingdom
8. Marketing Authorisation Number(S)
PL 04515/0111
9. Date Of First Authorisation/Renewal Of The Authorisation
23 November 2000
10. Date Of Revision Of The Text
11. Legal Category
POM
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