Etoposide 20 mg/ml concentrate for solution for infusion

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Etoposide
Available from:
Fresenius Kabi Deutschland GmbH
ATC code:
L01CB; L01CB01
INN (International Name):
Etoposide
Dosage:
20 milligram(s)/millilitre
Pharmaceutical form:
Concentrate for solution for infusion
Therapeutic area:
Podophyllotoxin derivatives; etoposide
Authorization status:
Marketed
Authorization number:
PA2059/036/001
Authorization date:
2014-05-16

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V001/BA

The following information

is intended for healthcare

professionals only:

Cytotoxic agent

Instructions on how to dilute, store

and dispose of etoposide

Dilution

Etoposide 20 mg/ml concentrate for

solution for infusion must be diluted

immediately prior to use with either

50 mg/ ml (5%) dextrose in water,

or 9 mg/ ml (0.9%) sodium chloride

solution to give a final concentration

of 0.2 mg/ml to 0.4 mg/ml. At higher

concentrations precipitation of

etoposide may occur.

Etoposide is administered by slow

intravenous infusion (usually over a

30 to 60 minute period). Etoposide

SHOULD NOT BE GIVEN

BY RAPID INTRAVENOUS

INJECTION.

Storage of the prepared solution

After dilution

Chemical and physical in-use

stability of the solution diluted to a

concentration of 0.2 mg/ml or

0.4 mg/ml has been demonstrated up

to 24 hours at 15°C to 25°C.

From a microbiological point of view,

the diluted 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 would normally not

be longer than 12 hours at 15°C to

25°C, unless dilution has taken place

in controlled and validated aseptic

conditions.

Handling and disposal

The normal procedures for proper

handling and disposal of anti-cancer

medicinal products should be adopted:

Staff should be trained to

reconstitute the medicinal product.

Pregnant staff should be excluded

from working with this medicinal

product.

Staff handling this medicinal

product during dilution should

wear protective clothing including

mask, goggles and gloves.

All items for administration or

cleaning, including gloves, should

be placed in high-risk, waste

disposal bags for high-temperature

incineration.

Accidental contact with the skin or

eyes should be treated immediately

with copious amounts of water.

Disposal

Any unused product or waste

material should be disposed

of in accordance with local

requirements.

Package leaflet: Information for the user

Etoposide 20 mg/ml

concentrate for solution for infusion

Etoposide

Read all of this leaflet carefully before you start using

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, ask your doctor or

nurse.

If you get any side effects, talk to your doctor or nurse.

This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet:

What etoposide is and what it is used for

What you need to know before you are given etoposide

How you will be given etoposide

Possible side effects

How to store etoposide

Contents of the pack and other information

1.

What etoposide is and what it is used for

name

this

medicine

‘Etoposide

mg/ml

concentrate for solution for infusion’ but in the rest of the

leaflet it will be called ‘etoposide’. It contains the active

ingredient etoposide. Etoposide belongs to the group of

medicines called cytostatics which are used in the treatment

of cancer.

Etoposide is used in the treatment of certain types of

cancers in adults:

testicular cancer

small cell lung cancer

cancer of the blood (acute myeloid leukaemia)

tumour in the lymphatic system (Hodgkin’s lymphoma,

non-Hodgkin’s lymphoma)

reproductive system cancers (gestational trophoblastic

neoplasia and ovarian cancer)

Etoposide is used in the treatment of certain types of

cancers in children:

cancer of the blood (acute myeloid leukaemia)

tumour in the lymphatic system (Hodgkin’s lymphoma,

non-Hodgkin’s lymphoma)

The exact reason why you have been prescribed etoposide

is best discussed with your doctor.

2.

What

you

need

to

know

before

you

are

given

etoposide

Do not take etoposide

if you are allergic to etoposide or any of the other

ingredients of this medicine (listed in section 6).

If you are breast-feeding or planning to breast-feed

If you have recently been given a live vaccine, including

Yellow fever vaccine.

If any of the above affects you, or if you are unsure if they

do, tell your doctor who will be able to advise you.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before you receive

etoposide:

if you have low levels of a protein called

albumin

your blood.

if you have had

radiotherapy

chemotherapy

recently

if you have any

infections

if you have liver or kidney problems.

Effective anti-cancer treatment can destroy cancer cells

rapidly in large numbers. On very rare occasions this may

cause harmful amounts of substances from these cancer

cells to be released into the blood. If this happens it can

cause problems with the liver, kidney, heart or blood,

which may result in death if not treated.

In order to prevent this, your doctor will need to do regular

blood tests to monitor the level of these substances during

treatment with this medicine.

This medicine can cause a reduction in the level of some

blood cells, which could cause you to suffer from infections,

or may mean that your blood doesn’t clot as well as it

should if you cut yourself. Blood tests will be taken at the

start of your treatment, and before each dose you take, to

make sure that this isn’t happening.

If you have reduced liver or kidney function, your doctor

may also want you to take regular blood tests to monitor

these levels.

Other medicines and etoposide

Tell your doctor if you are taking, have recently taken or

might take any other medicines.

This is especially important

if you are taking warfarin (a medicine used to prevent

blood clots from forming).

if you are taking a medicine called cyclosporin (a drug

used to reduce the activity of the immune system).

if you are being treated with cisplatin (a medicine used

to treat cancer).

if you are taking phenytoin or any other medicines used

to treat epilepsy.

if you are taking phenylbutazone, sodium salicylate, or

aspirin

if you have recently been given any live vaccines.

taking

anthracyclines

group

medicines used to treat cancer).

if you are taking any drugs with a similar mechanism of

action as etoposide.

Pregnancy, breast-feeding and fertility

If you are pregnant or breast-feeding, think you may be

pregnant or are planning to have a baby, ask your doctor for

advice before taking this medicine.

Pregnancy

Etoposide must not be used during pregnancy unless clearly

indicated by your doctor.

Breast-feeding

You must not breast-feed while you are receiving etoposide.

Fertility

Both male patients and female patients of child-bearing

age should use an effective contraceptive method (

e.g

., the

barrier method or condoms) during treatment and for at

least 6 months after the end of treatment with etoposide.

Male patients treated with etoposide are advised not to

father a child during treatment and for up to 6 months after

treatment. In addition, men are advised to seek counselling

on sperm preservation before starting treatment.

Both male and female patients who are considering having

a child after having treatment with etoposide should discuss

this with their doctor or nurse.

Driving and using machines

No studies on the effects on the ability to drive and use

machines have been performed. However, if you feel tired,

sick to your stomach, dizzy or light-headed you should not

do so until you have discussed it with your doctor.

Etoposide

contains

ethanol,

benzyl

alcohol

and

polysorbate 80

Ethanol

This

medicinal

product

contains

30.5

ethanol

(alcohol), which is corresponds to 241.4 mg of ethanol per

ml of concentrate, equivalent to 6.1 ml of beer, 2.5 ml of

wine. With a dose of 120 mg/m², 2.5 g ethanol is applied

to a patient with a body surface of 1.73 m², equivalent to

63.32 ml beer, 25.95 ml wine per dose.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding

women, children and high-risk groups such as patients with

liver disease, or epilepsy.

Benzyl alcohol

This medicine contains 30 mg benzyl alcohol per ml.

Benzyl alcohol may cause allergic reactions.

Ask your doctor for advice if you have liver or kidney

disease. This is because large amounts of benzyl alcohol

can build-up in your body and may cause side effects

(called “metabolic acidosis”).

Do not use for more than a week in young children (less than

3 years old), unless advised by your doctor or pharmacist.

Benzyl alcohol has been linked with the risk of severe

side effects including breathing problems (called “gasping

syndrome”) in young children. Do not give to your newborn

baby (up to 4 weeks old), unless recommended by your

doctor.

Polysorbate 80

Etoposide

contains

polysorbate

life

threatening

syndrome,

with

liver

kidney

failure,

decline

respiratory function, fall in platelet count and swelled

abdomen has been reported in premature infants when

administered polysorbate 80 containing vitamin E injection.

3.

How you will be given etoposide

Etoposide will be given to you by a doctor or nurse. It

will be given as a slow infusion into a vein. This may take

between 30 to 60 minutes.

The dose you receive will be specific to you, which the

doctor will calculate. The usual dose, based on etoposide,

is 50 to100 mg/m

body surface area, daily for 5 days in

a row or 100 to 120 mg/ m

body surface area on days 1,

3 and 5. This course of treatment may then be repeated,

depending on the results of blood tests, but this will not be

for at least 21 days after the first course of treatment.

For children being treated for cancer of the blood or

lymphatic system the dose used is 75 to 150 mg/m

body

surface area daily for 2 to 5 days.

doctor

sometimes

prescribe

different

dose

particularly if you are receiving, or have received, other

treatments for your cancer or if you have kidney problems.

If you are given more etoposide than you should

As a doctor or nurse will be giving you your medicine,

overdose is unlikely. However, if this does occur your

doctor will treat any symptoms that follow.

If you have any further questions on the use of this

medicine, ask your doctor or nurse.

4.

Possible side effects

Like all medicines, this medicine can cause side effects,

although not everybody gets them.

Tell your doctor or nurse immediately if you get any

of the following symptoms: swelling of your tongue or

throat, breathing difficulties, fast heartbeat, flushing

of the skin or a rash. These may be signs of a severe

allergic reaction.

Severe

liver, kidney or heart damage

from a condition

called tumour lysis syndrome, caused by harmful amounts

of substances from the cancer cells getting into the blood

stream, has been seen sometimes when etoposide is taken

along with other drugs used to treat cancer.

Possible side effects

experienced with etoposide that are;

Very common

: may affect more than 1 in 10 people

blood disorders (this is why you will be having blood

tests between courses of treatment)

temporary hair loss

nausea and vomiting

abdominal pain

loss of appetite

changes in skin colour (pigmentation)

constipation

feeling weak (asthenia)

generally feeling unwell (malaise)

damage to the liver(hepatotoxicity)

increased liver enzymes

jaundice (increased bilirubin)

Common

: may affect up to 1 in 10 people

acute leukaemia

irregular heart beat (arrhythmia), or a heart attack

(myocardial infarction)

dizziness

diarrhoea

reactions at the site of infusion

severe allergic reactions

high blood pressure

low blood pressure

sore lips, mouth or throat ulcers

skin problems such as itching or rash

inflammation of a vein

infection

Uncommon

: may affect up to 1 in 100 people

tingling or numbness in hands and feet

bleeding

Rare

: may affect up to 1 in 1,000 people

acid reflux

flushing

difficulty swallowing

a change in the way things taste

severe allergic reactions

convulsions (seizure)

fever

sleepiness or tiredness

breathing problems

temporary blindness

serious reactions of the skin and/or mucous membranes

which may include painful blisters and fever, including

extensive

detachment

skin

(Stevens-Johnson

syndrome and toxic epidermal necrolysis)

a sunburn-like rash that may occur on skin that has

previously been exposed to radiotherapy and can be

severe (radiation recall dermatitis)

Not

known

(frequency

cannot

estimated

from

available data)

tumour lysis syndrome (complications of substances

released from treated cancer cells entering the blood )

face and tongue swelling

infertility

difficulty breathing

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.

For UK

- You can also report side effects directly via the

Yellow Card Scheme at: www.mhra.gov.uk/yellowcard

For Ireland

- Reports may be made by completing the

downloadable report from the HPRA website and sending

it to:

HPRA Pharmacovigilance

Kevin O’Malley House, Earlsfort Centre

Earlsfort Terrace

IRL-Dublin

Tel: +35316764971

Fax: +35316762517

www.hpra.ie

medsafety@hpra.ie

reporting

side

effects

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.

Do not use this medicine after the expiry date which is

stated on the vial and carton after EXP. The expiry date

refers to the last day of that month.

This

medicinal

product

does

require

special

temperature storage conditions. Do not freeze. Store in the

original package, in order to protect from light.

Etoposide 20 mg/ml

xxxxxxxx / IRL/GBR

Etoposide 20 mg/ml

xxxxxxxx / IRL/GBR

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V001/BA

Do not store the diluted product in a refrigerator (2°C to

8°C) as this might cause precipitation. Solutions showing

any sign of precipitation should not be used.

After dilution

Chemical and physical in-use stability of the solution

diluted to a concentration of 0.2 mg/ml or 0.4 mg/ml has

been demonstrated up to 24 hours at 15°C to 25°C.

From a microbiological point of view, the diluted 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 would normally not be longer

than 12 hours at 15°C to 25°C, unless dilution has taken

place in controlled and validated aseptic conditions.

Do not throw away any medicines via wastewater or

household waste. Ask your pharmacist how to throw away

medicines you no longer use. These measures will help

protect the environment.

6.

Contents of the pack and other information

What etoposide contains

The active substance is Etoposide. Each 1 ml concentrate

for solution for infusion contains 20 mg of etoposide.

Each 5 ml vial contains 100 mg of etoposide.

Each 10 ml vial contains 200 mg of etoposide.

Each 25 ml vial contains 500 mg of etoposide.

Each 50 ml vial contains 1000 mg of etoposide.

The other ingredients are: macrogol 300, polysorbate

E433),

benzyl

alcohol

(E1519),

ethanol

anhydrous citric acid (E 330)

What etoposide looks like and contents of the pack

Etoposide is a clear, light yellow to pale yellow solution

packaged in type-I, clear, moulded glass vials of 5 ml,

10 ml, 30 ml and 50 ml, closed with 20 mm bromobutyl

rubber closure and sealed with 20 mm flip-off Aluminium

overseals (Green, Blue, Red and Yellow respectively).

Pack sizes:

Etoposide is available in packs containing

1 vial of 5 ml, 10 ml, 25 ml and 50 ml.

Not all pack sizes may be marketed.

Marketing Authorisation Holder

For UK:

Fresenius Kabi Oncology Plc.

Lion Court, Farnham Road, Bordon

Hampshire, GU35 0NF

United Kingdom

For IRL:

Fresenius Kabi Deutschland GmbH

Else-Kröner-Straße 1,

61352 Bad Homburg v.d.Höhe

Germany

Manufacturer:

Fresenius Kabi Deutschland GmbH

Pfingstweide 53

61169 Friedberg

Germany

This medicinal product is authorised in the Member

States of the EEA under the following names:

Austria

Etoposid Kabi 20 mg/ml Konzentrat zur

Herstellung einer Infusionslösung

Belgium

Etoposide Fresenius Kabi 20 mg/ml

concentraat voor oplossing voor infusie

Denmark

Etoposid Fresenius Kabi

Estonia

Etoposide Kabi 20 mg/ml

Spain

Etopósido Kabi 20mg/ml concentrado para

solución para perfusión

Finland

Etoposid Fresenius Kabi 20 mg/ml

infuusiokonsentraatti, liuosta varten

France

Etoposide Kabi 20 mg/ml solution à diluer

pour perfusion

Hungary

Etoposide Kabi 20 mg/ml koncentrátum

oldatos infúzióhoz

Ireland

Etoposide 20 mg/ml concentrate for

solution for infusion

Latvia

Etoposide Kabi 20 mg/ml koncentrāts

infūziju šķīduma pagatavošanai

Lithuania

Etoposide Kabi 20 mg/ml koncentratas

infuziniam tirpalui

Malta

Etoposide 20 mg/ml concentrate for

solution for infusion

Netherlands

Etoposide Fresenius Kabi 20 mg/ml

concentraat voor oplossing voor infusie

Norway

Etoposid Fresenius Kabi

Poland

Etoposide Kabi

Portugal

Etoposido Kabi

Romania

Etopozida Kabi 20 mg/ml concentrat

pentru soluţie perfuzabilă

Sweden

Etoposid Fresenius Kabi 20 mg/ ml

koncentrat till infusionsvätska, lösning

Slovenia

Etopozid Kabi 20 mg/ml koncentrat za

raztopino za infundiranje

Slovak

Republic

Etoposide Kabi 20 mg/ml, infúzny

koncentrát

United

Kingdom

Etoposide 20 mg/ml concentrate for

solution for infusion

This leaflet was last revised in March 2019

Health Products Regulatory Authority

29 July 2019

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Page 1 of 11

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Etoposide 20 mg/ml concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml concentrate for solution for infusion contains 20 mg of etoposide.

Each 5 ml vial contains 100 mg of etoposide.

Each 10 ml vial contains 200 mg of etoposide.

Each 25 ml vial contains 500 mg of etoposide.

Each 50 ml vial contains 1000 mg of etoposide.

Excipients with known effect:

Benzyl alcohol 30 mg/ml

Ethanol: 241.4 mg/ml

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

A clear, light yellow to pale yellow solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Testicular cancer

Etoposide is indicated in combination with other approved chemotherapeutic agents for the treatment of first line, recurrent or

refractory testicular cancer in adults.

Small cell lung cancer

Etoposide is indicated in combination with other approved chemotherapeutic agents for the treatment of small-cell lung

cancer in adults

Hodgkin's lymphoma

Etoposide is indicated in combination with other approved chemotherapeutic agents for the treatment of Hodgkin's lymphoma

in adult and paediatric patients

Non-Hodgkin's lymphoma

Etoposide is indicated in combination with other approved chemotherapeutic agents for the treatment of non-Hodgkin's

lymphoma in adult and paediatric patients.

Acute myeloid leukaemia

Etoposide is indicated in combination with other approved chemotherapeutic agents for the treatment of acute myeloid

leukaemia in adult and paediatric patients.

Gestational trophoblastic neoplasia

Etoposide is indicated for first line and second line therapy in combination with other approved chemotherapeutic agents for

the treatment of high risk gestational trophoblastic neoplasia in adults.

Ovarian cancer

Etoposide is indicated in combination with other approved chemotherapeutic agents for the treatment of non-epithelial

ovarian cancer in adults.

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Etoposide is indicated for the treatment of platinum-resistant/refractory epithelial ovarian cancer in adults.

4.2 Posology and method of administration

Etoposide should only be administered and monitored under the supervision of a qualified physician experienced in the use of

anti-neoplastic medicinal products (see section 4.4).

Posology

Adult population

The recommended dose of Etoposide in adult patients is 50 to 100 mg/m

/day (etoposide equivalent) on days 1 to 5 or 100 to

120 mg/m

on days 1, 3, and 5 every 3 to 4 weeks in combination with other drugs indicated in the disease to be treated.

Dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects

of prior radiotherapy or chemotherapy (see section 4.4) which may have compromised bone marrow reserve. The doses after

the initial dose should be adjusted if neutrophil count is below 500 cells/mm

for more than 5 days. In addition, the dose

should be adjusted in case of occurrence of fever, infections, or at a thrombocyte count below 25,000 cells/mm

, which is not

caused by the disease. Follow up doses should be adjusted in case of occurrence of grade 3 or 4 toxicities or if renal creatinine

clearance is below 50 ml/min. At decreased creatinine clearance of 15 to 50 ml/min a dose reduction by 25% is recommended.

Administration Precautions: As with other potentially toxic compounds, caution should be exercised in handling and preparing

the solution of etoposide. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is

recommended. If etoposide solution contacts the skin or mucosa, immediately wash the skin with soap and water and flush the

mucosa with water (see section 6.6)

Elderly population

No dosage adjustment is necessary in elderly patients (age > 65 years old), other than based on renal function (see section 5.2)

Paediatric population

Hodgkin's lymphoma; non-Hodgkin's lymphoma; acute myeloid leukaemia

Etoposide in paediatric patients has been used in the range of 75 to 150 mg/m

/day (etoposide equivalent) for 2 to 5 days in

combination with other antineoplastic agents. The treatment regimen should be chosen according to the local standard of care.

Ovarian cancer; small cell lung cancer; gestational trophoblastic neoplasia; testicular cancer

The safety and efficacy of Etoposide below 18 years of age have not been established. Currently available data are described in

section 5.2 but no recommendation on a posology can be made.

Renal impairment

In patients with impaired renal function, the following initial dose modification should be considered based on measured

creatinine clearance.

Measured Creatinine Clearance

Dose of Etoposide

>50 ml/min

100% of dose

15-50 ml/min

75% of dose

In patients with creatinine clearance less than 15 ml/min and on dialysis further dose reduction is likely to be required as

etoposide clearance is further reduced in these patients (see section 4.4). Subsequent dosing in moderate and severe renal

impairment should be based on patient tolerance and clinical effect (see section 4.4). Since etoposide and its metabolites are

not dialyzable, it can be administered pre- and post-haemodialysis (see section 4.9).

Method of administration

Etoposide is administered by slow intravenous infusion (usually over a 30 to 60 minute period) (see section 4.4).

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Lactation (see section 4.6.)

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

4.5).

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4.4 Special warnings and precautions for use

Etoposide should only be administered and monitored under the supervision of a qualified physician experienced in the use of

anti-neoplastic medicinal products. In all instances where the use of etoposide is considered for chemotherapy, the physician

must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are

reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate

corrective measures should be taken according to the clinical judgment of the physician. Reinstitution of etoposide therapy

should be carried out with caution, and with adequate consideration of the further need for the drug and close attention to

possible recurrence of toxicity.

Myelosuppression

Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy Fatal

myelosuppression has been reported following etoposide administration. Patients being treated with etoposide must be

observed for myelosuppression carefully and frequently both during and after therapy. The following haematological

parameters should be measured at the start of therapy and prior to each subsequent dose of etoposide: platelet count,

hemoglobin, white blood cell count and differential. If radiotherapy or chemotherapy has been given prior to starting

etoposide treatment, an adequate interval should be allowed to enable the bone marrow to recover.

Etoposide should not be administered to patients with neutrophil counts less than 1,500 cell/mm

or platelet counts less than

100,000 cells/mm

, unless caused by malignant disease.

Doses subsequent to initial dose should be adjusted if neutrophil count less than 500 cells/mm

occurs for more than 5 days or

is associated with fever or infection, if platelet count less than 25,000 cells/mm

occurs, if any other grade 3 or 4 toxicity

develops or if renal clearance is less than 50 ml/min.

Severe myelosuppression with resulting infection or haemorrhage may occur. Bacterial infections should be brought under

control before treatment with etoposide.

Secondary leukaemia

The occurrence of acute leukaemia, which can occur with or without myelodysplastic syndrome, has been described in patients

that were treated with etoposide containing chemotherapeutic regimens. Neither the cumulative risk, nor the predisposing

factors related to the development of secondary leukaemia are known. The roles of both administration schedules and

cumulative doses of etoposide have been suggested, but have not been clearly defined.

An 11q23 chromosome abnormality has been observed in some cases of secondary leukaemia in patients who have received

epipodophyllotoxins. This abnormality has also been seen in patients developing secondary leukaemia after being treated with

chemotherapy regimens not containing epipodophyllotoxins and in leukaemia occurring de novo. Another characteristic that

has been associated with secondary leukaemia in patients who have received epipodophyllotoxins appears to be a short

latency period, with average median time to development of leukaemia being approximately 32 months.

Hypersensitivity

Physicians should be aware of the possible occurrence of an anaphylactic reaction with etoposide, manifested by chills, pyrexia,

tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic. Etoposide should be

terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders

at the discretion of the physician.

Hypotension

Etoposide should be given only by slow intravenous infusion (usually over 30 to 60 minute, period) since hypotension has been

reported as a possible side effect of rapid intravenous injection.

Injection site reaction

Injection site reactions may occur during administration of etoposide. Given the possibility of extravasation, it is recommended

to closely monitor the infusion site for possible infiltration during drug administration

Low serum albumin

Low serum albumin is associated with increased exposure to etoposide. Therefore patients with low serum albumin may be at

increased risk for etoposide-associated toxicities.

Impaired renal function

In patients with moderate (CrCl =15 to 50 ml/min), or severe (CrCl <15ml/min) renal impairment undergoing haemodialysis,

etoposide 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.

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Page 4 of 11

Impaired hepatic function

Patients with impaired hepatic function should regularly have their hepatic function monitored due to the risk of accumulation.

Tumour lysis syndrome

Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other

chemotherapeutic drugs. Close monitoring of patients is needed to detect early signs of tumour lysis syndrome, especially in

patients with risk factors such as bulky treatment-sensitive tumours, and renal insufficiency. Appropriate preventive measures

should also be considered in patients at risk of this complication of therapy.

Excipient (s) that the clinician should be aware of:

Mutagenic potential

Given the mutagenic potential of etoposide, an effective contraception is required for both male and female patients during

treatment and up to 6 months after ending treatment. Genetic consultation is recommended if the patient wishes to have

children after ending the treatment. As etoposide may decrease male fertility, preservation of sperm may be considered for the

purpose of later fatherhood (see section 4.6)

Excipient (s) that the clinician should be aware of:

Ethanol

This medicinal product contains 30.5 % v/v ethanol (alcohol), which is corresponds to 241.4 mg of ethanol per ml of

concentrate, equivalent to 6.1 ml of beer, 2.5 ml of wine. With a dose of 120 mg/m², 2.50 g ethanol is applied to a patient with

a body surface of 1.73 m², equivalent to 63.32 ml beer, 25.95 ml wine per dose.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver

disease, or epilepsy.

Benzyl alcohol

Benzyl alcohol may cause allergic reactions.

High volumes should be used with caution and only if necessary, especially in subjects with liver or kidney impairment because

of the risk of accumulation and toxicity (metabolic acidosis).

Intravenous administration of benzyl alcohol has been associated with serious adverse events and death in neonates ("gasping

syndrome"). The minimum amount of benzyl alcohol at which toxicity may occur is not known.

Polysorbate 80

Etoposide Injection contains polysorbate 80. In premature infants, 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.

4.5 Interaction with other medicinal products and other forms of interactions

Effects of other drugs on the pharmacokinetics of etoposide

High dose cyclosporin, resulting in plasma 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, and other

enzyme-inducing antiepileptic therapy may be associated with increased etoposide clearance and reduced efficacy.

Caution should be exercised when administering etoposide with drugs that may reduce efficacy of etoposide.

In vitro plasma protein binding is 97%. Phenylbutazone, sodium salicylate and aspirin may displace etoposide from plasma

protein binding.

Effect of etoposide on the pharmacokinetics of other drugs

Co-administration of antiepileptic drugs and etoposide can lead to decreased seizure control due to pharmacokinetic

interactions between the drugs.

Co-administration of warfarin and etoposide may result in elevated international normalized ratio (INR). Close monitoring of

INR is recommended.

Pharmacodynamic interactions

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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 4.3).

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 4.4).

Cross resistance between anthracyclines and etoposide has been reported in preclinical experiments.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females

Women of childbearing potential should use appropriate contraceptive measures to avoid pregnancy during etoposide

therapy. Etoposide has been shown to be teratogenic in mice and rats (see section 5.3).

Given the mutagenic potential of etoposide, an effective contraceptive is required for both male and female patients during

treatment and up to 6 months after ending treatment (see section 4.4). Genetic consultation is recommended if the patient

wishes to have a children after ending 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 (see section 5.3). In general etoposide can cause fetal harm when administered to pregnant women.

Etoposide should not be used during pregnancy unless the clinical condition of the woman requires treatment with etoposide.

Women of childbearing potential should be advised to avoid becoming pregnant. Women of childbearing potential have to

use effective contraception during and up to 6 months after treatment. If this drug is used during pregnancy, or if the patient

becomes pregnant while receiving this drug, the patient should be informed of the potential hazard to the fetus.

Breast-feeding

Etoposide is excreted in human milk. There is the potential for serious adverse reactions in nursing infants from etoposide. A

decision must be made whether to discontinue breast-feeding or to discontinue etoposide, taking into account the benefit of

breast feeding for the child and the benefit of therapy for the woman (see section 4.3).

Benzyl alcohol is probably excreted into breast milk and can be orally absorbed by the infant.

Fertility

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

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. Etoposide 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. Patients who experience such adverse reactions should be advised to avoid driving

or using machines.

4.8 Undesirable effects

Summary of the safety profile

Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. In clinical studies in

which etoposide was administered as a single agent at a total dose of ≥ 450 mg/m

the most frequent adverse reactions of any

severity were leucopenia (91%), neutropenia (88%), anaemia (72%) thrombocytopenia (23%), asthenia (39%), nausea and/or

vomiting (37%), alopecia (33%) and chills and/or fever (24%).

Tabulated summary of adverse reactions

The following adverse reactions were reported from etoposide clinical studies and post-marketing experience. These adverse

reactions are presented by system organ class and frequency, which is defined by the following categories: Very common

(≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known (cannot be

estimated from the available data).

System Organ Class

Frequency

Adverse Reaction

(Medra Terms)

Infections and Infestations

Common

infection

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Neoplasms benign, malignant and unspecified (including cysts and polyps)

Common

acute leukaemia

Blood and lymphatic system disorders

Very

common

myelosuppression*,

leukopenia,

thrombocytopenia,

neutropenia,

anemia

Immune system disorders

Common

anaphylactic-

reactions**

Not known

Angioedema,

bronchospasm

Metabolism and nutrition disorders

Not known

tumour lysis

syndrome

Nervous system disorders

Common

dizziness

Uncommon

neuropathy

peripheral

Rare

seizure*** optic

neuritis, cortical

blindness transient,

neurotoxicities

(e.g., somnolence,

fatigue)

Cardiac disorders

Common

myocardial

infarction,

arrythmia

Vascular disorders

Common

transient systolic

hypotension

following rapid

intravenous

administration,

hypertension

Uncommon

haemorrhage

Respiratory, thoracic and mediastinal disorders

Rare

pulmonary fibrosis,

interstitial

pneumonitis

Not known

bronchospasm

Gastrointestinal disorders

Very

common

abdominal pain,

constipation,

nausea and

vomiting, anorexia

Common

mucositis

(including

stomatitis and

esophagitis),

diarrhoea

Rare

dysphagia,

dysgeusia

Hepato-biliary disorders

Very

common

hepatotoxicity,

alanine

aminotransferase

increased, alkaline

phosphatase

increased,

aspartate amino

transferase

increased, bilirubin

increased

Skin and subcutaneous tissue disorders

Very

common

alopecia,

pigmentation

Common

rash, urticaria,

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pruritus

Rare

stevens-Johnson

syndrome, toxic

epidermal

necrolysis,

radiation recall

dermatitis

Reproductive system and breast disorders

Not known

infertility

General disorders and administration site conditions

Very

common

asthenia, malaise

Common

extravasation****,

phlebitis

Rare

pyrexia

* Myelosuppression with fatal outcome has been reported.

** Anaphylactic reactions can be fatal.

***Seizure is occasionally associated with allergic reactions.

**** Postmarketing complications reported for extravasation included local soft tissue toxicity, swelling, pain, celullitis, 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 utilized

single agent etoposide therapy.

Hematological 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 or depending on the way of

administration and treatment scheme. Nadirs tend to occur earlier with intravenous administration compared to oral

administration.

Leucopenia and severe leucopenia (less than 1,000 cells/mm

) were observed in 91% and 17%, respectively, for etoposide/.

Thrombocytopenia and severe thrombocytopenia (less than 50,000 platelets/mm

) were seen in 2 3% and 9%, respectively, for

etoposide/. Reports of fever and infection were also very common in patients with neutropenia treated with etoposide.

Bleeding has been reported

Gastrointestinal Toxicity:

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

by antiemetic therapy

Alopecia:

Reversible alopecia, sometimes progressing to total baldness, has been observed in up to 44% of patients treated with

etoposide.

Hypotension:

Transient hypotension following rapid intravenous administration has been reported in patients treated with etoposide and has

not been associated with cardiac toxicity or electrocardiographic changes. Hypotension usually responds to cessation of

infusion of etoposide and/or other supportive therapy as appropriate. When restarting the infusion, a slower administration

rate should be used.

No delayed hypotension has been noted.

Hypertension:

In clinical studies involving etoposide, episodes of hypertension have been reported. If clinically significant hypertension

occurs in patients receiving etoposide, appropriate supportive therapy should be initiated.

Hypersensitivity:

Anaphylactic- reactions have 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

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pressure usually normalizes within a few hours after cessation of the infusion. Anaphylactic- reactions can occur with the initial

dose of etoposide.

Anaphylactic reactions, manifested by chills, tachycardia, bronchospasm, dyspnoea, diaphoresis, pyrexia, pruritus, hypertension

or hypotension, syncope, nausea, and vomiting have been reported to occur in 3% of patients treated with etoposide. Facial

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

cessation of the infusion and administration of pressor agents, 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 episodes in association with other

chemotherapeutic drugs. (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 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517.

Website: www.hpra.ie; e-mail: medsafety@hpra.ie.

4.9 Overdose

Total doses of 2.4 g/m

to 3.5 g/m

administered intravenously over three days have resulted in severe mucositis and

myelotoxicity.

Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended

intravenous doses of etoposide. Similar toxicities can be expected with oral formulation

A specific antidote is not available. Treatment should therefore be symptomatic and supportive, and patients should be closely

monitored.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cytostatics, plant alkaloids and other natural products; podophyllotoxin derivatives, ATC Code:

L01CB01

Mechanism of action

The main effect of etoposide appears to be at the late S and early G

portion of the cell cycle in mammalian cells. Two

dose-dependent responses are seen: At high concentrations (10 mcg/ml or more), cells entering mitosis are lysed; at low

concentrations (0.3 to 10 mcg/ml), cells are inhibited from entering prophase. Microtubule assembly is not affected. The

predominant macromolecular effect of etoposide seems to be the rupture of the double strand by an interaction with

DNA-topoisomerase II or by the formation of free radicals. Etoposide has been shown to cause metaphase arrest in chick

fibroblasts.

5.2 Pharmacokinetic properties

Absorption

After either intravenous infusion or oral capsule administration, the C

and AUC values exhibit marked intra- and

inter-subject variability.

Distribution

The mean volumes of distribution at steady state range from 18 to 29 liters. Etoposide shows low penetration into the CSF. In

vitro, etoposide is highly protein bound (97%) to human plasma proteins.

Etoposide binding ratio correlates directly with serum albumin in cancer patients and normal volunteers (see section 4.4).

Unbound fraction of etoposide correlates significantly with bilirubin in cancer patients.

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Biotransformation

The hydroxyacid metabolite [4' dimethyl-epipodophyllic acid-9-(4,6 0-ethylidene-β-D-glucopyranoside)], formed by opening of

the lactone ring, is found in the urine of adults and children. It is also present in human plasma, presumably as the trans isomer.

Glucuronide and/or sulfateconjugates of etoposide are also excreted in human urine. In addition, O-demethylation of the

dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

Elimination

On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life

of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours. Total body clearance values range from 33 to

48 ml/min or 16 to 36 ml/min/m

and, like the terminal elimination half-life, are independent of dose over a range 100 to 600

mg/m

. After intravenous administration of

C etoposide (100 to 124 mg/m

), mean recovery of radioactivity in the urine was

56% (45% of the dose was excreted as etoposide) and faecal recovery of radioactivity was 44% of the administered dose at 120

hours.

Linearity/non-linearity

Total body clearance and the terminal elimination half-life are independent of dose over a range 100 to 600 mg/m

. Over the

same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration

) values increase linearly with dose.

Renal impairment

Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and

higher steady state volume of distribution (see section 4.2).

Hepatic impairment

In adult cancer patients with liver dysfunction, total body clearance of etoposide is not reduced.

Elderly population

Although minor differences in pharmacokinetic parameters between patients ≤65 years and >65 years of age have been

observed, these are not considered clinically significant.

Paediatric population

In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of

etoposide is 7 to 10 ml/min/m

or about 35% of the total body clearance over a dose range of 80 to 600 mg/m

. Etoposide,

therefore, is cleared by both renal and nonrenal processes, i.e., metabolism and biliary excretion. The effect of renal disease on

plasma etoposide clearance is not known in children. In children, elevated SGPT levels are associated with reduced drug total

body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.

An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children.

Gender

Although minor differences in pharmacokinetic parameters between genders have been observed, these are not considered

clinically significant.

Drug interactions

In a study of the effects of other therapeutic agents on in vitro binding of

C etoposide to human serum proteins, only

phenylbutazone, sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations generally achieved in vivo

(see section 4.5).

5.3 Preclinical safety data

Chronic toxicity

Anaemia, leucopenia, and thrombocytopenia were observed in rats and mice, while dogs had mild reversible deterioration of

liver and kidney functions. The dose multiple (based on mg/m

doses) for these findings at the no-observed

adverse-effect-level in the preclinical studies were ≥ approximately 0.05 times compared to the highest clinical dose.

Historically, preclinical species have been more sensitive compared to humans towards cytotoxic agents. Testicular atrophy,

spermatogenesis arrest, and growth retardation were reported in rats and mice.

Mutagenicity

Etoposide is mutagenic in mammalian cells.

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Reproductive toxicity

In animal studies etoposide was associated with dose-related embryotoxicity and teratogenicity.

Carcinogenic potential

Given its mechanism of action, etoposide should be considered a possible carcinogen in humans.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Macrogol 300

Polysorbate 80 ( E433)

Benzyl alcohol (E1519)

Ethanol

Anhydrous citric acid (E 330)

6.2 Incompatibilities

Plastic devices made of acrylic or ABS polymers have been reported to crack when used with undiluted etoposide. This effect

has not been reported with etoposide after dilution of the concentrate for solution for infusion according to instructions.

This medicinal product must not be mixed with other medicinal product except those mentioned in section 6.6.

6.3 Shelf life

Vial before opening

2 years.

After dilution

Chemical and physical in-use stability of the solution diluted to a concentration of 0.2 mg/ml or 0.4 mg/ml has been

demonstrated up to 24 hours at 15°C to 25°C.

From a microbiological point of view, the diluted 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 would normally not be longer than 12 hours at 15°C to

25°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Do not freeze. Store in the original

package, in order to protect from light.

Do not store the diluted product in a refrigerator (2°C to 8°C) as this might cause precipitation.

Solutions showing any sign of precipitation should not be used.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

Type I, clear, moulded glass vials of 5 ml, 10 ml, 30 ml and 50 ml closed with 20 mm bromobutyl rubber closure sealed with 20

mm flip-off Aluminium overseals (Green, Blue, Red and Yellow respectively).

Pack sizes: Etoposide is available in packs containing 1 vial of 5 ml, 10 ml, 25 ml and 50 ml.

Not all pack sizes may be marketed.

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6.6 Special precautions for disposal and other handling

Etoposide should not be used without diluting. Dilute with 9 mg/ml (0.9%) sodium chloride or 50 mg/ml (5%) dextrose.

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 fluid should be avoided. During preparation and reconstitution a strictly aseptic working technique must be used;

protective measures must include the use of gloves, mask, safety goggles and protective clothing. Use of a vertical laminar

airflow (LAF) hood is recommended.

Gloves should be worn during administration. Cytotoxics should not be handled by pregnant personnel. Waste-disposal

procedures should take into account the cytotoxic nature of this substance.

If etoposide contacts skin, mucosae or eyes, immediately wash thoroughly with water. Soap may be used for skin cleansing.

Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Fresenius Kabi Deutschland GmbH

Else-Kroener Strasse 1

Bad Homburg v.d.H 61352

Germany

8 MARKETING AUTHORISATION NUMBER

PA2059/036/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 16

May 2014

Date of last renewal: 13

March 2019

10 DATE OF REVISION OF THE TEXT

July 2019

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