Etopex

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SHORT PRODUCT INFORMATION

1. NAME OF THE MEDICINAL PRODUCT
Vial containing ETOPEX 100 mg/5 ml concentrated solution for IV infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Active ingredient:
Each vial (5 ml) contains 100 mg of etoposide.
Excipients: Benzyl alcohol, citric acid anhydrous, absolute ethanol, polysorbate 80, PEG 300.
2 of
1 ml of ETOPEX contains 241 mg of ethanol. At a dose of 120 mg/m etoposide , a patient with a body surface
2
area of 1.6 m will receive 2.3 g of ethanol. It can be harmful for those with alcohol dependence. This amount
should be considered for pregnant and lactating women, children, and high-risk patients such as liver disease or
epilepsy, or patients taking disulfiram.
See section 6.1 for excipients.

3.PHARMACEUTICAL FORM
Vial containing concentrated solution for IV infusion

4. CLINICAL FEATURES
4.1. Therapeutic indications
Etoposide is an intravenous antineoplastic agent. It can be used alone or in combination with other antineoplastic
agents.
Etoposide can be used in combination with other chemotherapeutic agents with proven efficacy in small cell
lung cancer, and in combination with other chemotherapeutic agents with proven efficacy in patients who have
received appropriate surgery, chemotherapy or radiotherapy in the treatment of non-seminomatous testicular
carcinoma.
In addition, it has been shown that objective response can be obtained in the palliative treatment of non-small
cell lung cancer, re-induction treatment of Hodgkin's disease, induction treatment of non-Hodgkin lymphoma
(non-Hodgkin lymphoma) and acute myelocytic leukemia, and induction and re-induction treatment of chorion
carcinoma.

4.2. Posology and method of administration
Posology:
Adults:
Dosage depends on whether etoposide is given alone or in combination with other cytostatic agents.
2
Recommended dose ETOPEX consecutive IV daily for five days from 60 to 120 mg / m 'dir.
Application frequency and duration:
The solution should be given by intravenous infusion over a minimum of 30 minutes to 2 hours. Facial flushing
is a sign that the infusion rate is too high.
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Chemotherapy courses are repeated at intervals of 3-4 weeks after adequate recovery of any toxicity.
Because etoposide causes myelosuppression, treatment should not be repeated more often than at 3-week
intervals to allow leukocyte and platelet counts to return to normal. Before repeating a course of treatment with
ETOPEX infusion, the blood picture should be examined for signs of myelosuppression and treatment given if
satisfactory.
Method of Application:
ETOPEX should only be administered by healthcare professionals under the supervision of physicians
experienced in the use of cancer chemotherapeutic agents.
ETOPEX is used only by slow intravenous infusion. Etoposide should not be administered by injection into
body cavities (pleura, peritoneum and other).
Use only freshly prepared, colorless and clear solutions.
For detailed information about usage instructions and application, see section 6.6'.
Additional information on special populations:
Kidney failure:
In patients with renal insufficiency but with normal hepatic function, the dose of etoposide should be reduced
and hematological sub-values and renal functions should be monitored.
The recommended dosing regimen based on creatinine clearance is as follows:
Creatinine clearance Recommended daily dose (percentage of standard
(ml/min) dose)
>50 one hundred
15-50 75
<15 It is contraindicated (see Contraindications section).

Liver failure:
It should be used in patients with hepatic impairment by carefully adjusting the dose according to the severity of
the disease and hepatic impairment.
Pediatric population:
Efficacy and safety in children have not been established.
Geriatric population:
No dose adjustment is necessary.

4.3. Contraindications
Patients with hypersensitivity to any of the active ingredients or additives
Patients with severe hepatic insufficiency
Patients with severe renal impairment (creatinine clearance <15 ml / min)
3 3
Patients with severe myelosuppression (leukocyte ≤4000 /mm , platelet ≤1000 /mm )
breastfeeding mothers
Pregnancy period ( See section 4.6. Pregnancy and lactation .)
Intrathecal use

4.4. Special warnings and precautions for use

ETOPEX should only be administered by healthcare professionals under the supervision of physicians
experienced in the use of cancer chemotherapeutic agents.
ETOPEX should be given by slow intravenous infusion as rapid intravenous infusion may elicit a possible
hypotension reaction. The infusion time is 30 minutes to 2 hours. Extravasation may cause ulcerations and
necrosis. Facial flushing is a sign of too high an infusion rate.
Care should be taken as a possible anaphylactic reaction with flushing, chills, fever, tachycardia, bronchospasm,
dyspnea and hypotension may occur. Anaphylaxis-like reactions have been reported quite frequently in children
receiving infusion concentrations higher than recommended. In these cases, the infusion should be stopped
immediately, its treatment is symptomatic.
Patients treated with ETOPEX should be observed frequently for myelosuppression, both during and after
treatment. Dose-limiting bone marrow suppression is the most important toxicity associated with etoposide
therapy. If radiotherapy and/or chemotherapy has been given prior to initiating etoposide therapy, sufficient time
3
should be allowed to allow bone marrow recovery. The number of leukocytes 2,000 / mm 'or platelet count
3 3
50,000 / mm if' drops below elements of the blood circulating to an acceptable level (platelets 100,000 / mm 's
3
more, leukocytes 4,000 / mm ' s above) treatment is stopped until. Depending on whether etoposide is used
alone or in combination therapy, the blood picture normally resolves within 21 days. Peripheral blood count and
liver function should be monitored (see Undesirable effects section).
It should be prescribed in patients with leukemia and lymphoma only if the benefit outweighs the risk.
Antiemetics are useful for the control of nausea and vomiting seen in patients.
Bacterial and viral infections should be controlled prior to initiating etoposide therapy and close contact with
patients newly vaccinated with poliovirus vaccine should be avoided.
Etoposide should be administered with caution in patients receiving radiotherapy and chemotherapy, and in
patients with cardiac arrhythmia, previous myocardial infarction, hepatic dysfunction, renal dysfunction,
peripheral neuropathy, urination difficulties, epilepsy or brain injury or stomatitis.
Etoposide may exhibit genotoxic effects ( see section on preclinical safety data ).
Acute leukemia, which may also occur with a preleukemic phase, has been reported rarely in patients treated
with etoposide in combination with other antineoplastic drugs.
This medicinal product contains 30 mg of benzyl alcohol per vial. It should not be applied to premature babies
and newborns. May cause toxic reactions and anaphylactoid reactions in infants and children up to 3 years of
age.

4.5. Interactions with other medicinal products and other forms of interaction
Radiotherapy and administration of drugs that may induce myelosuppression may increase etoposide-induced
myelosuppression. Etoposide may increase the cytotoxic and myelosuppressant effects of other drugs (eg
cyclosporine). It was found that high dose cyclosporine treatment increased exposure to etoposide and decreased
etoposide clearance.
The effects of oral anticoagulants may be increased.
Phenylbutazone, sodium salicylate, and challic acid may affect the binding of etoposide to plasma proteins.
Cross-resistance between anthracyclines and etoposide has been demonstrated experimentally.

There are no data on the concomitant use of etoposide with drugs known to inhibit phosphatase activity (eg,
levamisole hydrochloride).
Do not use with alcohol.
Potentially useful interactions:
Etoposide is often used in combination with other cytotoxic drugs and it is assumed that they show a synergistic
effect in terms of cytotoxic effect, such a synergy has been demonstrated in vitro with some drugs such as
methotrexate and cisplatin.
A synergistic effect on tumor cells has been demonstrated in animal models with the following
chemotherapeutic agents: Cisplatin, carboplatin, mitomycin C, cyclophosphamide, BCNU, vincristine,
dactinomycin, and cytosine arabinoside.

4.6. pregnancy and lactation
Pregnancy category: D
General advice
ETOPEX should not be administered to pregnant or nursing mothers.
Women of childbearing potential/ Birth control (Contraception)
Women of childbearing potential should be advised to avoid becoming pregnant. Men and women of
childbearing potential should use an effective method of contraception throughout the treatment period and for 6
months after treatment. If a patient is planning to have a child following etoposide treatment, it is recommended
to consult a genetic specialist.
Pregnancy period
Etoposide is teratogenic in mice and rats at doses equivalent to clinically administered doses. Its safety during
use in pregnant women has not been established, and there are no adequate and controlled studies on its use in
pregnancy.
ETOPEX should not be used during pregnancy unless necessary. Caution should be exercised when
administered to pregnant women ( see section 5.3. Preclinical safety data ).
lactation period
ETOPEX should not be used during breastfeeding.
reproductive ability (fertility)
ETOPEX may cause decreased fertility. There is a possibility of irreversible infertility.

4.7. Effects on the ability to drive and use machines
Adverse reactions such as fatigue and transient cortical blindness indicate that patients are unsuitable for driving
and operating machinery immediately after etoposide therapy. The patient's ability to drive and use machines
may be impaired due to the ethanol in ETOPEX.

4.8. undesirable effects
Undesirable effects, according to organ classes; very common (≥1/10), common (≥1/100 to <1/10), uncommon
(≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), and very classified as rare (<1/10000).
Infections and infestations:

Rare
Fever and sepsis have been reported.
Diseases of the blood and lymphatic system:
very common
The dose-limiting toxicity of etoposide is myelosuppression, particularly leukopenia and thrombocytopenia.
Leukopenia was observed in 60-91% of the patients, and thrombocytopenia was observed in 28% of the patients.
The lowest leukocyte levels occur approximately 21 days after treatment, and the lowest level of platelets after
11-17 days. Approximately 40% of patients have a decrease in hemoglobin levels. Anemia is rare.
Widespread
Bleeding and infections following severe myelosuppression.
Rare
The occurrence of acute leukemia (with or without the preleukemic phase) has been reported in the treatment of
etoposide with other antineoplastic drugs.
Immune system diseases:
Unusual
Anaphylactic reactions characterized by chills, chills, flushing, fever, tachycardia, dyspnoea, bronchospasm, and
hypotension have been reported after the use of etoposide. The incidence of anaphylactic reactions is higher in
children who receive infusions at higher than recommended concentrations. However, the role of infusion
concentration (or infusion rate) in the development of anaphylactic reaction is uncertain. These reactions are
usually treated with discontinuation of the drug and, if necessary, vasopressor agents such as adrenaline,
corticosteroids, antihistamines, or plasma volume expanders. However, these reactions can be fatal.
A hypersensitivity reaction may develop due to the benzyl alcohol contained in ETOPEX. Hypertension,
flushing, swelling of the face/tongue, cough, sweating, cyanosis, throat tightness, laryngospasm,
unconsciousness, rarely apnea have been reported.
Very rare
Two cases of Stevens Johnson have been described in the literature; however, its association with etoposide has
not been proven. Fatal toxic epidermal necrosis was observed in one case.
Metabolism and nutrition diseases:
Rare
Hyperuricemia has been reported.
Nervous system diseases:
Widespread
Peripheral neuropathy was seen in 0.7-2% of cases.
Unusual
convulsion.
Rare
Confusion, hyperkinesia, somnolence, drowsiness, fatigue, aftertaste, and temporary cortical blindness may
occur as a result of the central nervous system being affected.
Cardiac diseases:
Very rare
Myocardial infarction and arrhythmias have been reported after the use of etoposide, a link with etoposide has
not been established.
Vascular diseases:
Widespread
Hypotension may occur after rapid infusion and resolves with decreasing infusion rate.
Unusual
Hypertension and flushing (fever) have also been reported. Blood pressure returns to normal within a few hours
after discontinuation of the infusion. Phlebitis may be seen.
Respiratory, thoracic and mediastinal disorders:
Unusual
Apnea reverting to spontaneous breathing has been reported after discontinuation of etoposide therapy.
Immediate, fatal reactions associated with bronchospasm have been reported. Pneumonia has been seen rarely.
Cough, laryngospasm and cyanosis, interstitial pneumonia / pulmonary fibrosis may occur.
Gastrointestinal diseases:
very common
Nausea and vomiting occur in approximately 30-40% of patients. Anti-emetics are useful in controlling these
side effects.
Rare
Abdominal pain, diarrhea, constipation, loss of appetite, esophagitis and stomatitis (oral mucositis) may occur.
Dysphagia has been reported. At high doses, oral mucositis can be dose-limiting.
Hepato-biliary diseases:
Unusual
Etoposide has been shown to reach high concentrations in the liver and kidneys, so accumulation is possible if
dysfunction occurs in these organs. Increases in liver enzymes have been reported after high doses of etoposide.
Skin and subcutaneous tissue diseases:
very common
Reversible alopecia, sometimes up to complete baldness, is seen in about 66% of patients.
Unusual
Edema of the face and tongue, sweating.
Rare
Rash, urticaria, pigmentation and pruritus (pyruritus) may occur after etoposide administration.
Very rare
Dermatitis similar to that induced by radiation has been reported in a single case.
Kidney and urinary diseases:
Etoposide has been shown to reach high concentrations in the kidneys and is therefore likely to accumulate in
the event of dysfunction.
Reproductive system and breast diseases:
Amenorrhea, anovulatory cycles, decreased fertility and hypomenorrhoea.

4.9. Overdose and its treatment

Overdose:
2
Intravenously total of 2.4-3.5 g / m / day, more than 3 days at doses resulting in severe mucositis and
myelotoxicity. Metabolic acidosis and severe hepatic toxicity have been reported in patients receiving higher
than recommended doses of etoposide.
Treatment:
The efficacy of tried antidotes against etoposide overdose has not been established. Symptomatic and supportive
treatment should be done.
The risk of infection and the severity of neutropenia can be minimized by administering hematopoietic growth
factor when leukopenia is at its peak.
Supportive treatment includes:
Nausea, vomiting: antiemetics
Allergic reactions: discontinuation of etoposide therapy, corticosteroids, sympathomimetics,
antihistamines, plasma expanders
Bronchospasm: Aminophylline, corticosteroids
Hypotension: discontinuation of etoposide therapy, fluid and plasma expanders
Hyperuricemia: Allopurinol

5. PHARMACOLOGICAL PROPERTIES
5.1. Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents/podophyllotoxin derivatives. ATC code: L01CB01. Etoposide
is a semi-synthetic, lipophilic podophyllotoxin derivative. Etoposide acts as an antineoplastic and cytotoxic
agent. It affects topoisomerase II (DNA opening enzyme) enzyme and thus inhibits DNA synthesis in the
terminal phase of topoisomerase action. This results in the breaking of single and double DNA strands. Its
effectiveness is based on the induction of single and double breaks in the DNA chain through intracellular
binding of free radicals and interaction with the enzyme topoisomerase II. Cell death is dependent on etoposide
concentration and time of administration. Etoposide effect is specific to the cell period, and most cells S and
early G stops in the period. The cytotoxic effect in resting cells was seen only at high concentrations.
2

5.2. Pharmacokinetic properties
General features:
The pharmacokinetics of etoposide show significant individual variability.
Absorbation:
In terms of its pharmaceutical form and application site, the drug mixes directly into the blood.
Distribution:
It shows rapid distribution. The mean volume of distribution is approximately 32% of body weight. Mean
2
volume of distribution at steady state 18-29 L or 7-17 L / m fall in the range. Etoposide passes poorly into the
CSF. Although it can be detected in CSF and intracerebral tumors, its concentrations there are lower than those
in extracerebral tumors and plasma. Etoposide concentrations are higher in normal lung than in lung metastases
and are similar to those in primary tumors and normal myometrial tissue.
It is highly bound to plasma proteins in human serum (94%). In a study to determine the effect of other
therapeutic drugs on the binding of C14-labeled etoposide to human serum proteins in vitro, only
phenylbutazone, sodium salicylate, challic acid, and aspirin were replaced by protein-bound etoposide at
concentrations achieved in vivo.
The binding rate of etoposide is directly related to the serum albumin concentration in normal volunteers and
cancer patients. In other words, the data show a significant inverse relationship between serum albumin
concentration and the free etoposide fraction.
Biotransformation:
The major urinary metabolite of etoposide in adults or children is the 4-hydroxy acid metabolite formed by
opening the lactone ring [4'-demethylepipodophylic acid-9-(4,6-O-(R)-ethylidene-bD-glucopyranoside)]. It is
also found in human plasma as the trans isomer.
In humans, 5-22% of the ingested dose is excreted in the urine as glucuronide and/or sulfate conjugates. In
addition, O-demethylation of the dimethoxyphenol ring to form the appropriate catechol occurs via the CYP450
3A4 isoenzyme pathway. After intravenous infusion, Cmax and AUC values vary markedly in the same
individual and between individuals.
Elimination:
Clearance of etoposide from plasma shows bi-exponential kinetics and fits a two-compartment model.
Distribution of etoposide by IV administration is a biphasic process with an optimal distribution half-life of 1.5
hours and a terminal elimination half-life of 4 to 11 hours. Total body clearance values of 33 to 48 ml / min or 16
2 2
to 36 ml / min / m between. Terminal half-life and total body clearance of 100 to 600 mg / m at the dose was
not dose-dependent over the range. The AUC and maximum plasma concentration values of plasma
concentration with respect to time increase linearly with dose over the same dose range. Daily for 4-5 days
2
etoposide 100 mg / m after application, does not accumulate in plasma.
2
After intravenous administration of 3H-etoposide (70-290 mg/m ), the radioactivity excreted in the urine is
between 42-67% of the ingested dose and 0-16% of the radioactivity excreted in the feces. Approximately 45%
of the intravenous dose and 2/3 of it is excreted unchanged in the urine within 72 hours. Etoposide mean renal
2 2
clearance of 7 to 10 ml / min / m or 80 to 600 mg / m 'ligand is about 35% of the total body clearance in a
dose range. Therefore, etoposide is cleared from the body both by the kidneys and by non-renal means such as
metabolism and excretion with bile. Biliary excretion appears to be a very low pathway for etoposide
elimination. Only 6% or less of the intravenous dose is found in the bile as etoposide. Metabolism is responsible
for most of the extrarenal clearance of etoposide.
In adults, body clearance of total etoposide is related to creatinine clearance, serum albumin concentration, and
non-renal clearance. Patients with reduced renal function have decreased total body clearance, increased AUC,
and a lower volume of distribution at steady state. Cisplatin therapy is associated with reduced total body
clearance.
Characteristics in patients:
Age:
Although minor differences in pharmacokinetic parameters were observed between different age groups, these
are not considered to be clinically significant.
Gender:
Although minor differences in pharmacokinetic parameters were observed between the sexes, these are not
considered to be clinically significant.
Pediatric patients:
There is an inverse relationship between plasma albumin levels and renal clearance of etoposide in children.
Elevated serum SGPT levels are associated with decreased total drug body clearance. Prior use of cisplatin
results in a reduction in total body clearance of etoposide in children.
Approximately 50% of the dose taken in children is excreted in the urine as etoposide within 24 hours.
Kidney failure:
Patients with reduced renal function have decreased total body clearance, increased AUC, and a lower volume of
distribution at steady state.

5.3. Preclinical safety data
Mutagenicity:
Etoposide is mutagenic and genotoxic in mammalian cells. There are positive in vitro and in vivo tests showing
that etoposide is mutagenic and causes mutations at the gene and chromosome level . Etoposide caused
abnormalities in chromosome number and structure in embryonic murine cells and human hematopoietic cells,
chain breaks, DNA damage and DNA-protein cross-links in Chinese hamster ovary cells and mouse leukemia
cells, as well as dose-dependent increase in chromatid pairs exchange in Chinese hamster ovary cells.
Reproductive toxicity (teratogenicity):
Etoposide is teratogenic in rats at doses corresponding to those used in clinical practice. It has been shown to be
teratogenic and embryotoxic in mice and rats at 1 to 3% of the recommended clinical dose based on body
surface area. SPF rats 6-15 weeks of gestation. Dose-related maternal toxicity, embryotoxicity (prenatal
mortality, fetal resorptions, low fetal weight), and teratogenicity (major skeletal abnormalities, exencephaly,
encephalocele, and anophthalmia) have been reported with intravenous administration of 0.4, 1.2, and 3.6 mg/kg
of etoposide on The dose of 0.13 mg/kg caused an increase in delayed ossification. Dose-related embryotoxicity
(intrauterine fetal death, low fetal weight) and teratogenicity (cranial anomalies, major skeletal anomalies) were
also reported with intraperitoneal administration of 1, 1.5, or 2 mg/kg to Swiss-Albino mice on the 6th, 7th, or
8th day of gestation.
Carcinogenicity:
Animal studies demonstrating the carcinogenicity of etoposide have not yet been performed. However, based on
its DNA damage and mutagenicity potential, etoposide should be considered potentially carcinogenic in humans.

6. PHARMACEUTICAL PROPERTIES
6.1. List of excipients
Polysorbate 80
PEG 300
Citric Acid Anhydrous

Absolute ethanol
Benzyl alcohol

6.2. incompatibilities
ETOPEX should not be diluted in buffered solutions with a pH greater than 8 because the likelihood of
precipitate formation increases.
It should only be reconstituted with isotonic sodium chloride or isotonic glucose solutions suitable for infusion.
Etoposide concentration in the prepared solution should not exceed 0.4 mg/ml in case of precipitation.

6.3. Shelf life
24 months

6.4. Special warnings for storage
Store the vial at room temperature below 25 °C, protected from light. The solution diluted with one of the
solvents of 5% dextrose and 0.9% NaCl should be used for IV infusion within 24 hours when stored at room
temperature protected from light.

6.5. The nature and content of the packaging
Colorless Type 1 glass, gray bromobutyl rubber stopper, vial with aluminum cap and flip-off cap. Each
cardboard box contains 1 vial.

6.6. Disposal of residues from the medicinal product for human use and other special measures
It should be disposed of in accordance with the 'Medical waste control regulation' and 'Packaging and packaging
waste control regulations'.
As with all cytotoxic agents, etoposide should be handled with extreme care; Gloves, face mask and protective
clothing should be worn. If possible, etoposide should be kept under a fume hood. Contact with skin and mucous
membranes should be avoided. Pregnant hospital personnel should not administer etoposide.
If the eyes are contaminated, the eyes should be washed with plenty of water, and a doctor's help should be
sought if necessary.
Care should be taken and precautions should be taken in the disposal of objects (needles, syringes, etc.) used
during re-administration of cytotoxic drugs. Residual materials and body wastes should be disposed of in
0
double-lock polyethylene bags and incinerated at 1000 C. Liquid wastes should be cleaned with plenty of
pressurized water.

7. LICENSE OWNER
Deva Holding A.Ş.
Halkali Merkez Mah. Basin Ekspres Cad.
No: 1 34303
Kucukcekmece/ISTANBUL
Tel: 0 212 692 92 92

Fax: 0 212 697 00 24

8. LICENSE NUMBER
237/22

9. FIRST LICENSE DATE/LICENSE RENOVATION DATE
First license date: 18.11.2011
License renewal date:

10. RENEWAL DATE OF SCU
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12/1/21, 3:45 PM https://translate.googleusercontent.

SHORT PRODUCT INFORMATION

4.4. Special warnings and precautions for use

Cross-resistance between anthracyclines and etoposide has been demonstrated experimentally.

Infections and infestations:

4.9. Overdose and its treatment

Citric Acid Anhydrous

Tel: 0 212 692 92 92

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