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ETOPOSIDE 20MG/ML INJECTION

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Etoposide 20 mg/ml Sterile Concentrate

2.

Qualitative and Quantitative Composition

Each ml contains 20mg Etoposide
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, nonseminomatous testicular carcinoma.

4.2

Posology and method of administration
Etoposide is administered by slow intravenous infusion only (see below).
Etoposide 20mg/ml concentrate for solution for infusion is to be diluted before
use (see Section 6.6; Instructions for Use and Handling).
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.
Paediatrics:

Safety and effectiveness in children have not been established.

Elderly:

No dosage adjustment is necessary.

Renal Impairment: 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:
Creatinine Clearance
(ml/min)
>50
15-50
<15

Recommended Daily Dose
(% of standard dose)
100
75
Contraindicated
(see
Contraindications).

Section

4.3;

The diluted solution for Intravenous Infusion prepared according to the
instructions in section 6.6 should be given by slow intravenous infusion over a
period of not less than 30 minutes. Care should be taken to avoid
extravasation.
4.3

Contraindications
Etoposide is contraindicated in:





4.4

Patients who have demonstrated hypersensitivity to the active substance or
to any of the excipients.
Patients with severe hepatic impairment.
Patients with severe renal impairment (creatinine clearance <15ml/min.
See Section 4.2; Posology and Method of Administration).
Patients with severe myelosuppression.

Special warnings and precautions for use
Etoposide should only be administered by healthcare professionals
experienced in the use of antineoplastic therapy.
Etoposide must not be administered intra-arterially or into cavities (pleura,
peritoneum or other cavities).
When etoposide is administered intravenously care should be taken to avoid
extravasation.

If radiotherapy and/or chemotherapy have 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 or platelet count less than
50,000/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). Depending on whether etoposide is used in
monotherapy or combination therapy, circulating blood levels typically
recover within 21 days.
Peripheral blood counts and liver function should be monitored (see Section
4.8; Undesirable Effects).
Bacterial infections should be brought under control before treatment with
etoposide commences.
Anaphylactic reactions manifested by flushing, tachycardia, bronchospasm,
and hypotension may occur (see Section 4.8; Undesirable Effects).
Nausea and vomiting occur in approximately 30-40% of patients. Anti-emetics
are useful in controlling these undesirable effects.
Etoposide can have genotoxic effects (see Section 5.3; Preclinical Safety
Data). Therefore men being treated with etoposide are advised not to father a
child during and up to 6 months after treatment. There is a possibility of
irreversible infertility.
Tumour lysis syndrome (sometimes fatal) has been reported following 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.
Cardiac toxicity may occur when etoposide is used at higher than
recommended doses with other agents at a high dose.
4.5

Interactions with other medicinal products and other forms of interaction
Etoposide may potentiate the cytotoxic and myelosuppressive action of other
agents.
The action of oral anticoagulants can be increased.
Phenylbutazone, sodium salicylate and salicylic acid can affect protein binding
of etoposide.
There are no data on administering etoposide with medicinal products that are
known to inhibit phosphatase activity (eg, levamisole hydrochloride).

Potentially useful interactions
Etoposide is commonly used in association with other cytotoxic agents and
synergistic effects are thought to occur in most instances in terms of cytotoxic
effect. Such synergism has been substantiated in vitro for certain medicinal
products, including methotrexate and cisplatin.
4.6

Pregnancy and lactation
Pregnancy: The safe use of etoposide in pregnancy has not been established.
Women of childbearing potential should be advised to avoid becoming
pregnant. Caution should be exercised when prescribing to pregnant women
(see Section 5.3; Preclinical Safety Data).
Lactation: Etoposide should not normally be administered to mothers who are
breast feeding.

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
Blood and Lymphatic System Disorders: 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.
The occurrence of acute leukaemia, which can occur with or without a preleukaemic phase has been reported rarely in patients treated with etoposide in
association with other anti-neoplastic medicinal products.
Nervous System Disorders: The use of etoposide has been reported
infrequently to cause both peripheral neuropathy and central nervous system
effects including; confusion, hyperkinesia, akinesia, somnolence, dizziness,
fatigue, aftertaste and transient cortical blindness.
Cardiac and Vascular Disorders: Hypotension may occur following an
excessively rapid infusion and may be reversed by slowing the infusion rate.
Hypertension and/or flushing have also been reported. Blood pressure usually
returns to normal within a few hours after cessation of the infusion.
Myocardial infarction and rhythm disorders have been reported infrequently
following the use of etoposide.

Respiratory Disorders: Apnoea with spontaneous resumption of breathing
following discontinuation of etoposide has been reported. Sudden fatal
reactions associated with bronchospasm have been reported. Pneumonia and
pneumonitis have been reported rarely.
Gastrointestinal Disorders: Nausea and vomiting are the major
gastrointestinal toxicities and occur in approximately 30-40% of patients (see
Section 4.4; Special Warnings and Special Precautions for Use). Abdominal
pain, diarrhoea, constipation, anorexia, oesophagitis and stomatitis occur
infrequently.
Hepato-biliary Disorders: Etoposide has been shown to reach high
concentrations in the liver and kidney, thus presenting a potential for
accumulation in cases of functional impairment. Following high doses of
etoposide, increases in liver enzymes have been reported.
Skin and Subcutaneous Tissue Disorders: Reversible alopecia sometimes
progressing to complete baldness has occurred in approximately 66% of
patients. Stevens-Johnson syndrome, rash, urticaria, pigmentation and pruritus
have been reported rarely following the administration of etoposide. A single
case of radiation recall dermatitis has been reported.
General Disorders: Anaphylactoid reactions characterised by chills, flushing,
tachycardia, bronchospasm and hypotension have been reported following
administration of etoposide. Higher rates of anaphylactoid reactions have
been reported in children who received infusions at higher concentrations of
etoposide 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, e.g. adrenaline (epinephrine), corticosteroids,
antihistamines or volume expanders as appropriate.
Fever has been infrequently reported with the use of etoposide and sepsis has
been reported rarely.
Hyperuricemia has been reported rarely with the use of etoposide.
Neoplasms benign, malignant and unspecified: Tumour lysis syndrome
(sometimes fatal) has been reported rarely (see Section 4.4 Special Warnings
and Special Precautions for Use).
4.9

Overdose
No proven 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
Pharmacotherapeutic group:
derivatives (ATC: L01C B01).

Antineoplastic

products/podophyllotoxin

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 concentration of etoposide and exposure period.
Etoposide is phase specific, with cells being arrested in S and 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 plasma. Plasma decay kinetics follow a bi-exponential curve and
correspond 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 approximately
45% of an administered dose, two thirds being excreted unchanged in 72
hours. Phenylbutazone, sodium salicylate and salicyclic acid can affect
protein binding of etoposide.

5.3

Preclinical Safety Data
Toxicity to Reproduction: Etoposide is teratogenic in rats at dose levels
equivalent to those in clinical use.
Mutagenicity: There are positive results from in vitro and in vivo tests with
regard to gene and chromosome mutations induced by etoposide indicating
that it is mutagenic.
Carcinogenicity: Tests have not been performed in animals to determine the
carcinogenicity of etoposide. However, based on the DNA damaging effect
and the mutagenic potential, etoposide should be considered a potential
carcinogen in humans.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Citric acid (anhydrous)
Polysorbate 80
Macrogol 300
Ethanol (anhydrous)

6.2

Incompatibilities
The medicinal product must not be mixed with other medicinal products
except those mentioned in section 6.6.

6.3

Shelf Life
Product as packaged for sale: 2 years
Following dilution: 6 hours

6.4

Special Precautions for Storage
Do not store above 25oC.
Keep container in the outer carton in order to protect from light.
Following dilution: Chemical and physical in-use stability has been
demonstrated for 6 hours at 23oC. 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 normally not exceed 24 hours at 2 – 8oC, unless dilution has taken
place in controlled and validated aseptic conditions.

6.5

Nature and Contents of Container
Type I glass vials (colourless) with rubber closures.
Package containing 5 vials with 5ml each.
Package containing 5 vials with 10ml each.
Package containing 1 vial with 50ml each.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling
For single use only.
The preparation of the solution for infusion must be performed in aseptic
conditions.
Immediately prior to administration, the required amount of Etoposide
20mg/ml concentrate for solution for infusion must be diluted with 0.9%
sodium chloride solution or 5% glucose solution for intravenous
administration to give a concentration of not more than 0.25mg Etoposide per
ml. The diluted solution is administered by slow intravenous infusion (see
Section 4.2; Posology and Method of Administration).
The concentration of Etoposide should not exceed 0.25mg/ml because at
higher concentrations precipitation may occur.
Only clear solutions without visible particles should be used.
The diluted solutions for intravenous infusion prepared according to the
instructions above are compatible with glass or PVC containers.
Guidelines for the safe handling and disposal of antineoplastic agents:
1.

Trained personnel should dilute the concentrate.

2.

This should be performed in a designated area.

3.

Adequate protective gloves should be worn.

4.

Precautions should be taken to avoid the medicinal product accidentally
coming into contact with the eyes. In the event of contact with the eyes,
irrigate with large amounts of water and/or 0.9% sodium chloride
solution.

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 and/or dilute cytotoxic
medicinal products. Any unused product or waste material should be
disposed of in accordance with local requirements.

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

Hospira UK Limited
Queensway
Royal Leamington Spa
Warwickshire
CV31 3RW
UK
8.
MARKETING AUTHORISATION NUMBER
PL 04515/0111

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/11/2005

10

DATE OF REVISION OF THE TEXT
22/11/2005

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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