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ETOPOSIDE FOR INJECTION CONCENTRATE 20MG/ML

Active substance(s): ETOPOSIDE / ETOPOSIDE / ETOPOSIDE

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• Adults (including the elderly)
60-120 mg/m2 daily for five days.
• Children
Etoposide is not recommended for use in
children.
• Patients with liver or kidney problems
Your dose may be altered by your doctor.
If you receive more Etoposide than you should
As a doctor or nurse will be giving you your
medicine, it is unlikely that you will receive an
incorrect dose. Tell your doctor or nurse if you
have any concerns about the amount of medicine
that you receive.
If you have any further questions on the use of
this product, ask your doctor or nurse.

4

Possible side effects

Like all medicines, this medicine can cause side
effects, although not everybody gets them.
The following side effects may occur at the
approximate frequencies shown:
Very common (may affect more than 1 in 10
people)
Common (may affect up to 1 in 10 people)
Uncommon (may affect up to 1 in 100 people)
Rare (may affect up to1 in 1,000 people)
Very rare (may affect up to 1 in 10,000 patients)
Not known: frequency cannot be estimated from
the available data.
A few people may experience rare but serious
side effects when using this medicine. If you
experience any of the following, tell your doctor
immediately:
• difficulty breathing, wheezing, shortness of
breath, low blood pressure
• fever, chills, faster heart beat
• Stevens-Johnson syndrome (blistering of the
skin, mouth, eyes and genitals)
• toxic epidermal necrolysis (blistering of the
skin)
• tumour lysis syndrome (a side effect of
chemotherapy that occurs when cancer cells
break down too quickly) usually when
etoposide is given with another anticancer
drug. The symptoms of this may include a salt
imbalance which could cause heart failure,
severe muscle weakness, paralysis, kidney
failure, spasms of the hands and feet, seizures,
mental retardation, memory loss, movement
disorders, anxiety, agitation, swelling of the
optic disc, or increased levels of uric acid in the
blood which may lead to kidney failure.
Etoposide contains polysorbate 80. In premature
infants, injection of a vitamin E product
containing polysorbate 80 has led to a life
threatening syndrome occurring.
The following side effects have been reported at
the appropriate frequencies shown. If you
experience any of these effects and they get
serious or worry you, please tell your doctor or
nurse as soon as possible.
Very common (affecting more than one person in
ten):
• myelosuppression (a reduction in the ability of
the bone marrow to produce blood cells)
resulting in a reduction in the number of white
blood cells, clotting cells and red blood cells,
causing infections, bleeding or bruising, pale
skin, weakness or breathlessness
• feeling sick, being sick, loss of appetite
• hair loss (reversible on stopping Etoposide
treatment)
• skin colouring
• abdominal pain
• constipation
• liver problems, abnormal liver enzymes
• general weakness (asthenia), malaise.
Common (affecting more than one person in one
hundred but fewer than one person in ten):
• blood cancer (secondary leukemia)
• hypersensitivity (anaphylactic-like reactions)
• dizziness
• irregular heart beat and heart attack
• drop in blood pressure after an infusion is
administered too rapidly (can be prevented by
reducing the rate of the infusion).
• inflammation of the gastric and oesophageal
mucous membrane (mucositis, oesophagitis)
• rash, nettle rash, itchy skin
• swelling of the face or tongue

• stomach, throat, tongue and mouth ulcers, cold
sores
• coughing, sweating, difficulty in catching your
breath
• breathlessness, tiredness, sleepiness
• high or low blood pressure
• diarrhoea
• unexplained bleeding in patients with severe
myelosuppression (a condition in which bone
marrow activity is decreased, resulting in fewer
red blood cells, white blood cells, and platelets)
• leaking of fluid outside the vessel
(extravasation)
• inflammation of a vein (also known as
thrombophlebitis) sometimes accompanied by
a clot.
Uncommon (affecting more than one person in
one thousand but fewer than one person in one
hundred):
• discolouration of skin
• tingling or numbness in the hands and feet,
possibly aggravated by taking vincristine and
Etoposide at the same time.
Rare (affecting more than one person in ten
thousand but fewer than one person in one
thousand):
• insults (seizure, occasionally associated with
allergic reactions),
• lethargy
• taste impairment
• problems with eye sight
• pneumonia,
• scarring of the lungs which causes shortness of
breath
• difficulty swallowing
• localised death of the skin creating blisters
(toxic epidermal necrolysis)
• radiation recall phenomenon (redness and
itching at the site of previous radiation)
• redness and swelling of the palms of your
hands or soles of your feet which may cause
your skin to peel (hand-foot syndrome).
Reporting of side effects
If you get any side effects, talk to your doctor,
pharmacist or nurse. This includes any possible
side effects not listed in this leaflet. You can also
report side effects directly via the Yellow Card
Scheme at: www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide
more information on the safety of this medicine.

5

How to store Etoposide

Keep this medicine out of the sight and reach of
children.
Etoposide should be stored below 25°C. It should
be kept in the package or container supplied. Do
not transfer it to another container.
Do not use Etoposide after the expiry date that is
stated on the outer packaging. The expiry date
refers to the last day of that month.
The diluted solution should be discarded within
8 hours of preparation.

6

Contents of the pack and other
information

What Etoposide concentrate for solution for
infusion contains:
• The active ingredient is etoposide.
• The other ingredients are citric acid,
polysorbate 80, ethanol, macrogol 300.
What Etoposide concentrate for solution for
infusion looks like and contents of the pack:
• Etoposide concentrate for solution for infusion
is a clear, yellow, slightly viscous solution in
clear, colourless glass vials.
• Etoposide concentrate for solution for infusion
is available in vials of 5 ml, 10 ml, 20 ml, 25 ml
and 50 ml.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and
Manufacturer
Marketing Authorisation holder: TEVA UK
Limited, Eastbourne, BN22 9AG.
Company responsible for manufacture:
Pharmachemie BV, Haarlem, The Netherlands.
This leaflet was last revised: May 2015
PL 00289/0473
67862-R

Nervous System Disorders

Very common neurotoxicities (e.g.,
somnolence, fatigue)
Common

Vascular Disorders

Respiratory, Thoracic and
Mediastinal Disorders

Gastrointestinal Disorders

Dizziness

Uncommon

Neuropathy peripheral

Rare

Seizure***** optic
neuritis, transient cortical
blindness
Haemorrhage, transient
systolic hypotension
following rapid intravenous
administration,
hypertension

Common

Uncommon

Bronchospasm, coughing,
laryngospasm

Rare

Pulmonary fibrosis,
interstitial pneumonitis,
apnoea

Very common Abdominal pain,
constipation, nausea and
vomiting, anorexia
Common

Rare

Very common Hepatotoxicity

Skin and Subcutaneous Tissue

Very common Alopecia, pigmentation

General Disorders and
Administration Site Conditions

Investigations

5.2

Mucositis (including
stomatitis and esophagitis),
diarrhoea
Dysphagia, dysgeusia

Hepatobiliary Disorders
Disorders

5.
5.1

Common

Rash, urticaria, pruritus

Rare

Stevens-Johnson
syndrome, toxic epidermal
necrolysis, radiation recall
dermatitis, hand foot
syndrome

Very common Asthenia, malaise
Common

Extravasation******,
phlebitis, fatigue

Not known

Increase in bilirubin,
SGOT and alkaline
phosphatases (High
dosages)

*

This leukaemia is characterised with a relatively short latency period,
monocytic or myelomonocytic FAB subtype, chromosomal abnormalities at
11q23 in about 50% and a good response to chemotherapy. A total
cumulative dose (etoposide > 2 g/m²) is associated with increased risk (see
section “special warnings and precautions for use”).
**
Etoposide is also associated with development of acute promyelocytic
leukemia (APL). High doses of etoposide (> 4,000 mg/m²) appear to
increase the risk of APL.
***
Myelosuppression with fatal outcome has been reported.
****
Anaphylactic-type reactions can be fatal.
***** Seizure is occasionally associated with allergic reactions.
****** Post-marketing complications reported for extravasation included local soft
tissue toxicity, swelling, pain, cellulitis, and necrosis including skin necrosis.

Description of selected adverse reactions
In the paragraphs below the incidences of adverse events, given as the mean
percent, are derived from studies that utilised single agent etoposide therapy.
Haematological Toxicity:
Myelosuppression 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
60-91% and 7-17%, respectively, for etoposide or etoposide phosphate.
Thrombocytopenia and severe thrombocytopenia (less than 50,000
platelets/mm3) were seen in 28-41% and 4-20%, respectively, for
etoposide/etoposide phosphate. Reports of fever and infection were also very
common in patients with neutropenia treated with etoposide /etoposide
phosphate.
Gastrointestinal Toxicity:
Nausea and vomiting are the major gastrointestinal toxicities of etoposide. The
nausea and vomiting can usually be controlled by antiemetic therapy. They have
been noted in 31-43% of patients given intravenous etoposide. Anorexia was
seen in 10-13% of patients and stomatitis in 1-6% of those patients given
intravenous etoposide. Diarrhoea was noted in 1-13% of these patients.
Alopecia:
Reversible alopecia, sometimes progressing to total baldness, has been observed
in up to 66% of patients treated with etoposide and 44% of patients treated
with etoposide phosphate.
Blood Pressure Changes
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.
Allergic Reactions:
Anaphylactic-type reactions have also 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-type
reactions is uncertain. Blood pressure usually normalises within a few hours after
cessation of the infusion. Anaphylactic-type reactions can occur with the initial
dose of etoposide.
Acute fatal reactions associated with bronchospasm have been reported with
etoposide. Facial flushing was reported in 2% of patients and skin rashes in 3%
treated with etoposide phosphate.
Metabolic Complications:
Tumour lysis syndrome (sometimes fatal) has been reported following the use of
etoposide in association with other chemotherapeutic drugs.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal
product is important. It allows continued monitoring of the benefit/risk balance
of the medicinal product. Healthcare professionals are asked to report any
suspected adverse reactions via the Yellow Card Scheme at:
www.mhra.gov.uk/yellowcard
4.9 Overdose
Acute overdosage results in severe forms of normally occurring adverse
reactions, in particular leucopenia and thrombopenia. Severe mucositis and
elevated values of serum bilirubin, SGOT and alkaline phosphatase have been

5.3

6.
6.1

6.2
6.3

6.4

6.5

6.6

7.
8.
9.
10.

reported after administration of high doses of etoposide (total dosages of 2.4 to
3.5 g/m² etoposide, administered intravenously over three days).
Metabolic acidosis and severe hepatic toxicity have been reported after
administration of dosages higher than recommended.
The management of bone marrow depression is symptomatic, including
antibiotics and transfusions.
If hypersensitivity to etoposide occurs, antihistamines and intravenously
administered corticosteroids are appropriate. A specific antidote is not available.
Treatment should therefore be symptomatic and supportive, and patients
should be closely monitored.
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Cytostatics – Podophyllotoxin – derivative
ATC code: L01CB01.
Etoposide is a semisynthetic derivative of podophyllotoxin.
Its main effect appears to be at the G2 portion of the cell cycle. Two
dose-dependent responses occur: at high concentrations (equal or more
than 10 μg/ml), lysis of cells entering mitosis is seen; at low concentrations
(0.3-10 μg/ml), cells are inhibited from entering prophase. The predominant
macromolecular effect appears to be DNA synthesis inhibition.
Pharmacokinetic properties
Absorption/Distribution
On I.V. administration, the disposition of etoposide is a biphasic process with a
distribution half-life of about 1.5 hours and terminal elimination half-life ranging
from 4-11 hours. Total body clearance values range from 33-48 ml/min and, like
the terminal elimination half-life, are independent of dose. The area under the
plasma concentration-time curves (AUC) and maximum plasma concentration
(Cmax) values increase linearly with dose. Etoposide does not accumulate in the
plasma following daily I.V. administration of 100 mg/m² for 4-5 days. After I.V.
infusion, Cmax and AUC values exhibit marked intra-subject and intersubject
variability.
The mean volumes of distribution at steady state range from 18-29L. Although
detectable in CSF and intracerebral tumors, the concentrations are lower than in
extracerebral tumours and plasma. Concentrations are higher in normal lung
than in lung metastases and are similar in primary tumours and normal tissues
of the myometrium. In vitro, etoposide is highly bonded (97%) to human
plasma proteins. An inverse relationship between plasma albumin levels and
renal clearance is found in children.
Metabolism/Excretion
Less than 50% of an I.V. dose is excreted in the urine as etoposide, with mean
recoveries of 8-35% within 24 hours (approximately 55% in children). The
mean renal clearance is 7-10 ml/min/m², or about 35% of the total body
clearance over a dose range of 80-600 mg/m². Etoposide is cleared by both
renal and nonrenal processes i.e. metabolism and biliary excretion. In patients
with renal dysfunction plasma etoposide clearance is decreased.
Only 6% or less of an I.V. dose is recovered in the bile as etoposide.
Metabolism accounts for most of the nonrenal clearance. The major urinary
metabolite is the hydroxy acid. Glucuronide or sulphate conjugates of etoposide
are excreted in human urine and represent 5-22% of the dose.
In adults, the total body clearance of etoposide is correlated with creatinine
clearance, serum albumin concentration and nonrenal clearance. In children,
elevated serum ALT levels are associated with reduced drug total body clearance.
Prior use of cisplatin may result in a decrease of etoposide total body clearance.
Preclinical safety data
Etoposide has been shown to be embryotoxic and teratogenic in rats and mice.
There are positive results from in vitro and in vivo tests with regard to gene and
chromosome mutations induced by etoposide. The results justify the suspicion
of a mutagenic effect in humans.
Carcinogenicity tests with etoposide have not been conducted in laboratory
animals. Etoposide should be considered a potential carcinogen in humans
based on the DNA damaging effect and the mutagenic potential.
PHARMACEUTICAL PARTICULARS
List of excipients
Citric acid
Polysorbate 80
Ethanol
Macrogol 300
Incompatibilities
In the absence of compatibility studies, this medicinal product must not be
mixed with other medicinal products.
Shelf-life
Shelf-life of the medicinal product as packaged for sale: 3 years
Shelf-life after dilution: 8 hours
The infusion has been shown to be physically and chemically stable to up to
120 hours at 25°C. However, in light of microbiological considerations, it is
recommended that the infusion be prepared centrally in a hospital pharmacy
department and should be discarded within 8 hours.
Etoposide concentrate for infusion is stable for up to 72 hours (3 days) at 25°C
following piercing of the rubber stopper. It is therefore suitable for multidose
use.
Special precautions for storage
Special precautions for storage of the medicinal product as packaged for sale.
Do not store above 25°C.
Store in the original package.
Special precautions for storage of the medicinal product after dilution:
Do not store above 25°C.
Special precautions for storage after first opening the concentrate for solution:
Do not store above 25°C.
Multi-dose use
Etoposide Concentrate for Infusion is stable for up to 72 hours (3 days) at 25°C
following piercing of the rubber stopper.
After dilution
The infusion has been shown to be physically and chemically stable for up to
120 hours at 25°C. However, in light of microbiological considerations, it is
recommended that the infusion be prepared centrally in a hospital pharmacy
department and should be discarded within 8 hours.
Nature and contents of container
Clear, colourless glass vial, closed with chlorobutyl grey siliconised stopper (20
mm, coated with black teflon) held by an aluminium crimped cap with flip-top
plastic disc.
Pack sizes:
All presentations are packaged as individual vials.
Not all pack sizes may be marketed in all member states.
Special precautions for disposal and other handling
Do not autoclave.
Etoposide should not be used without diluting. Solutions showing any signs of
precipitation should not be used. For waste-disposal and safety information,
guidelines on safe-handling of antineoplastic drugs should be followed. Any
contact with the solution should be avoided. During preparation and dilution a
strictly aseptic working technique should be used. Protective measures should
include the use of gloves, mask, safety goggles and protective clothing. Use of
a vertical laminar air flow hood is recommended. Gloves should be worn during
administration. If etoposide contacts skin, mucosae or eyes, immediately wash
thoroughly with water. Soap may be used for skin cleaning. Any unused
product or waste materials should be disposed of in accordance with the local
requirements.
MARKETING AUTHORISATION HOLDER
TEVA UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex,
BN22 9AG.
MARKETING AUTHORISATION NUMBER
PL 0289/0473
DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
31/08/2009
DATE OF REVISION OF THE TEXT
To be completed on approval

67862-R
93.130.385-K

93.130.385-K
The following information is intended for medical or healthcare professionals only:

Etoposide Concentrate for
Solution for Infusion 20 mg/ml
1. NAME OF THE MEDICINAL PRODUCT
Etoposide Concentrate for Solution for Infusion 20 mg/ml
QUALITATIVE AND QUANTITATIVE COMPOSITION
1 ml of concentrate for solution for infusion contains 20 mg etoposide.
A vial of 5 ml contains 100 mg of etoposide.
A vial of 10 ml contains 200 mg of etoposide.
A vial of 20 ml contains 400 mg of etoposide.
A vial of 25 ml contains 500 mg of etoposide.
A vial of 50 ml contains 1000 mg of etoposide.
Excipient(s) with known effect:
Ethanol anhydrous: 241 mg/ml
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear yellowish, slightly viscous solution.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Etoposide is an antineoplastic drug 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 and resistant non-seminomatous testicular
carcinoma. Use in children: safety and effectiveness in children have not been
established.
4.2 Posology and method of administration
This preparation is for intravenous administration. Etoposide is administered by
slow intravenous infusion. ETOPOSIDE SHOULD NOT BE GIVEN BY RAPID
INTRAVENOUS INJECTION.
Administration Precautions: Hypotension following rapid intravenous
administration has been reported. Hence it is recommended that the etoposide
solution be administered over a 30- to 60-minute period. Longer infusion times
may be required based on patient tolerance. 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. If etoposide solution contacts
the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap
and water.
Dosage: For all the indications the recommended course of Etoposide
Concentrate for Infusion is 60-120 mg/m², I.V., daily for five consecutive days.
Maximum dose per cycle: 650 mg/m2. As etoposide produces myelosuppression,
courses may not be repeated more frequently than at 21-day intervals. In any
case, repeated courses of etoposide should not be given until the blood picture
has been checked for evidence of myelosuppression and found to be satisfactory.
The required dose of etoposide concentrate must be diluted with either 5%
dextrose solution for injection or 0.9% saline solution for injection to give a
final concentration of 0.2 mg/ml of etoposide; it should then be given by
intravenous infusion over a period of not less than 30 minutes and not more
than 2 hours.
Dose adjustments
Dosage of etoposide should be modified to take into account the
myelosuppressive effects of other drugs in the combination or the effects of
prior X-ray therapy or chemotherapy which may have compromised bone
marrow reserve.
Patients should not begin a new cycle of treatment with etoposide if the
neutrophil count is less than 1,500 cells/mm3 or the platelet count is less than
100,000 cells/mm3, unless caused by malignant disease.
Doses subsequent to the 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 other grade
3 or 4 toxicity develops or if renal clearance is less than 50 ml/min.
In combination therapy the dosage of etoposide should be adjusted according
to the corresponding plan.
The duration of therapy is determined by the physician, taking into account the
underlying disease, the combined regimen administered (if applicable) and the
individual therapeutic situation. Etoposide should be discontinued when the
tumour does not respond or when progressive disease or intolerable toxicity
occurs.
Care should be taken to avoid extravasation.
Older people: no dosage adjustment is necessary.
In patients with renal function impairment the dose should be adjusted. In
patients with a measured creatinine clearance of greater than 50 mL/minute, no
initial dose modification is required. In patients with a measured creatinine
clearance of 15-50 mL/minute, 75% of the initial recommended etoposide dose
should be administered. In patients with a measured creatinine clearance less
than 15 mL/minute, no data are available and further dose reductions should be
considered in these patients.
Since etoposide-induced hematologic toxicity appeared to be more severe in
patients with elevated serum bilirubin concentrations in one study and there is
some evidence that total plasma clearance and elimination of the drug may be
reduced in patients with impaired hepatic function, etoposide should probably
be used with caution and the need for dosage reduction considered in patients
with hepatic impairment.
4.3 Contraindications
• Severe myelosuppression, unless when this is caused by the underlying
disease.
• Severe hepatic impairment
• Hypersensitivity to the active substance or to any of the excipients listed in
section 6.1.
• Concomitant use of yellow fever vaccine or other live vaccines is
contraindicated in immunosuppressed patients (see section “Interaction
with other medicinal products and other forms of interaction”).
4.4 Special warnings and precautions for use
Etoposide should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents. Injection site
reactions may occur during the administration of etoposide. Given the
possibility of extravasation, it is recommended to closely monitor the infusion
site for possible infiltration during drug administration. A specific treatment for
extravasation reactions is unknown at this time.
Severe myelosuppression with resulting infection or bleeding may occur.
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. Dose limiting bone
marrow suppression is the most significant toxicity associated with etoposide
therapy. The following studies should be obtained 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 the 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 other grade
3 or 4 toxicity develops or if renal clearance is less than 50 ml/min. Dosage
should be modified to take into account the myelosuppressive effects of other
drugs in the combination or the effects of prior radiation therapy or
chemotherapy which may have compromised bone marrow reserve.
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
2.

4.5

4.6

4.7

4.8

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.
Physicians should be aware of the possible occurrence of an anaphylactic
reaction with etoposide, manifested by chills, fever, tachycardia, bronchospasm,
dyspnea and hypotension, which can be fatal. Treatment is symptomatic. The
infusion should be terminated immediately, followed by the administration of
pressor agents, corticosteroids, antihistamines, or volume expanders at the
discretion of the physician.
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. It should not be injected intraarterially,
intrapleurally, or intraperitoneally.
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.
Patients with low serum albumin may be at increased risk for
etoposide-associated toxicities. Patients with impaired hepatic and renal
function should regularly have their renal and hepatic function monitored due
to the risk of accumulation.
Bacterial infections should be brought under control before treatment with
etoposide. Great care should be taken on giving etoposide to patients who
have, or have been exposed to infection with herpes zoster.
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. As etoposide may
decrease male fertility, preservation of sperm may be considered for the purpose
of later fatherhood (see section “Pregnancy and lactation”).
Paediatric population
Safety and effectiveness of etoposide in pediatric patients have not been
systematically studied.
Etoposide injections contain 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. This product contains 24% m/v of ethanol.
Each 5 ml vial contains up to 1,2 g of alcohol, each 25 ml vial contains up to 6 g
of alcohol. This can be harmful for those suffering from liver disease,
alcoholism, epilepsy, brain injury or disease as well as for children and pregnant
women. Alcohol also may modify or increase the effect of other medicines.
Interaction with other medicinal products and other forms of interaction
High dose cyclosporine, resulting in concentrations above 2000 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
compared to etoposide alone.
Concomitant cisplatin therapy is associated with reduced total body clearance
of etoposide.
Concomitant phenytoin therapy is associated with increased etoposide
clearance and reduced efficacy.
Concomitant warfarin therapy may result in elevated international normalized
ratio (INR). Close monitoring of INR is recommended.
There is increased risk of fatal systemic vaccinal disease with the use of yellow
fever vaccine. Live vaccines are contraindicated in immunosuppressed patients.
(See section “Contraindications”.)
Prior or concurrent use of other drugs with similar myelosuppressant action as
etoposide/etoposide phosphate may be expected to have additive or synergetic
effects (see section “Special warnings and precautions for use”).
In vitro plasma protein binding is 97%. Phenylbutazone, sodium salicylate, and
aspirin may displace etoposide from plasma protein binding.
Cross resistance between anthracyclines and etoposide has been reported in
preclinical experiments.
The occurrence of acute leukaemia, which can occur with or without a
preleukaemic phase has been reported in patients treated with etoposide in
association with other anti-neoplastic drugs, e.g. bleomycin, cisplatin,
ifosfamide, methotrexate.
Fertility, pregnancy and lactation
Pregnancy and women of child-bearing potential
Etoposide can cause fetal harm when administered to pregnant women.
Etoposide have been shown to be teratogenic in mice and rats.(see section
“preclinical safety data”). There are no adequate and well controlled studies in
pregnant women. Women of childbearing potential should be advised to avoid
becoming pregnant. If these drugs are used during pregnancy, or if the patient
becomes pregnant while receiving these drugs, the patient should be apprised
of the potential hazard to the fetus.
Contraception in males and females
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. As etoposide may
decrease male fertility, preservation of sperm may be considered for the purpose
of later fatherhood.
Breast-feeding
It is not known whether these drugs are excreted in human milk. Because many
drugs are excreted in human milk and because of the potential for serious
adverse reactions in nursing infants from etoposide, a decision should be made
whether to discontinue nursing or to discontinue the drug, taking into account
the importance of the drug to the mother.
Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed with etoposide. If the patient experiences side effects such as fatigue
and somnolence they should avoid driving or operating machines.
Undesirable effects
The following frequencies have been used:
• Very common (>1/10)
• Common (>1/100, <1/10)
• Uncommon (>1/1,000, <1/100)
• Rare (>1/10,000, <1/1,000)
• Very rare (<1/10,000)
• Not known (cannot be estimated from the available data)

Neoplasms Benign and Malignant Common
Not known
(including cysts and polyps)
Blood and the Lymphatic System
Disorders*

Cardiac Disorders

Immune System Disorders

Acute leukaemia*
Acute promyelocytic
leukaemia**

Very common Myelosuppression***,
leukopenia,
thrombocytopenia,
neutropenia, anaemia
Common

Myocardial infarction,
arrhythmia

Uncommon

Cyanosis

Common

Anaphylactic-type
reactions****

continued overleaf ...

Package leaflet: Information for the user

Etoposide concentrate for solution for
infusion 20 mg/ml
Read all of this leaflet carefully before you are
given this medicine because it contains
important information for you.
• Keep this leaflet. You may need to read it
again.
• If you have any further questions, please ask
your doctor or pharmacist.
• If you get any side effects, talk to your doctor
or pharmacist. This includes any possible side
effects not listed in this leaflet. See section 4.
What is in this leaflet:

1. What Etoposide is and what it is used for
2. What you need to know before you use
Etoposide
3. How to use Etoposide
4. Possible side effects
5. How to store Etoposide
6. Contents of the pack and other information

1

What Etoposide is and what it is
used for

Etoposide is an anti-cancer drug which is used to
treat certain types of cancer, in particular small cell
lung cancer and testicular cancer.
Etoposide may be given on its own or in
combination with other drugs.

2

What you need to know before you
use Etoposide

Do NOT use Etoposide if you:
• are allergic (hypersensitive) to etoposide or any
of the other ingredients of this medicine (listed
in section 6).
• are allergic (hypersensitive) to podophyllotoxin
or podophyllotoxin-derivatives
• if you have severe suppression of the
functioning of the bone marrow, unless when
this is caused by your disease
• will receive yellow fever vaccine or other live
vaccines. Live vaccines should not be used in
patients in which the immune system is less
functional.
• suffer from severe liver problems.
Warnings and precautions
Talk to your doctor before you use Etoposide
Etoposide is only used under strict supervision of
a doctor experienced with the use of cytostatics.
Tell your doctor if you have previously been
treated with products against cancer or if you
have received radiation therapy.
Etoposide should be only administered in a vein.
If you have a stinging or burning sensation at the
place where you have been injected with
Etoposide, it may be due to leaking of Etoposide
out of the vein. If this happens please tell your
doctor as they will start treatment from a different
vein and will monitor the affected area carefully.
Your doctor will regularly check your blood and
the functioning of your liver during the use of
Etoposide.
If you have bone marrow depression caused by
radiation therapy or chemotherapy, your doctor
will not restart the treatment until your blood
tests shows that this is justified.
Also tell your doctor if you think that you have
infections.
If you think that you might have an allergic
reaction causing flushing, fast heartbeat, difficulty
in breathing and a severe reduction in blood
pressure (anaphylactic reaction). Tell your doctor
immediately of these symptoms, you may need
urgent medical attention.
During and for 6 months after the use of
Etoposide both men and women must use
products to prevent pregnancy. Because
Etoposide can cause infertility, men can have their
sperm frozen at the sperm bank before the
treatment with Etoposide starts.
Consult your doctor if one of the above warnings
is applicable to you, or has been in the past.
Other medicines and Etoposide
Please tell your doctor nurse if you are taking,
have recently taken or might take any other
medicines:

• phenytoin (a product used in the treatment of
epilepsy). The concomitant use of Etoposide and
phenytoin can reduce the effect of Etoposide
• myelosuppressive drugs (these affect the bone
marrow) e.g. cyclophosphamide, carmustine,
lomustine, 5-fluorouracil, vinblastine
• yellow fever vaccine or other live vaccines
• any other anticancer drugs used to kill cancer
cells e.g. bleomycin, cisplatin, ifosfamide,
methotrexate, vinorelbine, daunorubicin,
doxorubicin, epirubicin and idarubicin
• non-steroidal anti-inflammatory drugs
(NSAIDs) such as phenylbutazone, sodium
salicylate or aspirin
• drugs to thin the blood, such as warfarin
• ciclosporin (a drug that suppresses the body’s
defence system)
• Etoposide and anthracyclines (products against
cancer) can negatively affect each other’s action.
Pregnancy and breast-feeding
• Etoposide is not recommended if you are
pregnant, planning to become pregnant or
breast-feeding. However, your doctor may
decide that the benefit you will receive from
treatment with this medicine outweighs the
risks to your unborn child.
• Because many drugs are excreted in human
milk and because of the potential for serious
adverse reactions in nursing infants from
Etoposide, a decision should be made whether
to discontinue nursing or to discontinue the
drug, taking into account the importance of the
drug to the mother.
• Female patients of child bearing age should use
an effective method of contraception, e.g. the
barrier method or condoms, to avoid getting
pregnant during treatment and for up to 6
months after treatment, as the drug may cause
serious birth defects.
• Male patients receiving treatment with
Etoposide should also take adequate
contraception precautions to ensure that their
partner does not become pregnant while they
are being treated and for up to 6 months after
treatment and might want consider having
their sperm frozen, as this medicine may cause
impaired fertility.
• Both male and female patients who are
considering having a child after the treatment
should discuss this with their doctor or nurse.
Driving and using machines
• Etoposide may cause nausea, vomiting,
drowsiness, tiredness, low blood pressure
resulting in dizziness, and allergic reactions such
as difficulty in breathing and a fast heart rate. If
affected do not drive or operate machinery.
• Etoposide contains alcohol. You should take
care if you need to drive immediately after
having an Etoposide injection.
Important information about some of the
ingredients of Etoposide
• A bottle with Etoposide contains 24% m/v
alcohol .This can be harmful for those suffering
from alcoholism. This must also be taken into
account in pregnant and breast-feeding
women, children and high-risk groups such as
patients with liver disease, diseases of the brain
or epilepsy.
• The amount of alcohol in this medicine may
alter the effects of other medicines and may
also impair your ability to drive or use
machines.

3

How to use Etoposide

Etoposide will be given to you by a suitably
experienced doctor or nurse and you will have
regular tests to monitor your condition.
The required dose of Etoposide concentrate for
solution for infusion will be diluted with either 5%
dextrose solution for injection or 0.9% saline
solution to give the correct concentration. Your
medicine will then be given to you by slow
intravenous infusion (an injection into the vein)
usually over a 30 to 60 minute period and not
more than 2 hours.
The duration of your treatment will be decided by
the doctor. Your doctor may consider it necessary
to give you a repeat course of Etoposide.
The dosage for Etoposide is estimated on your
body surface area in square metres (m2) calculated
from your height and weight. The usual dose is:

Expand Transcript

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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