New Zealand - English - Medsafe (Medicines Safety Authority)
Page 1 of 11
NEW ZEALAND DATA SHEET
QUALITATIVE AND QUANTITATIVE COMPOSITION
Etoposide is a semi-synthetic derivative of podophyllotoxin.
Etoposide Injection contains Etoposide, citric acid, polysorbate 80, Macrogol 300, and
Excipient(s) with known effect
For the full list of excipients, see section 6.1.
DBL® Etoposide Injection is available as a clear, colourless to pale yellow viscous liquid, in
clear glass vials.
Solution for injection
4.1 Therapeutic indications
Etoposide Injection is indicated for use in the treatment of:
Small cell carcinoma of the lung.
Acute monocytic and myelomonocytic leukaemia.
4.2 Dose and method of administration
Biological activity appears to be schedule dependent with multiple dosage over 3 or 5 days
showing superiority over single dose administration.
Page 2 of 11
Intravenous: Intravenously, 50-60 mg/m
/day for 5 days followed by a treatment-free interval
of 2-4 weeks.
Total dose should not exceed 400 mg/m
Intravenous Infusion (0.9%) or 5% Glucose Injection to give a final concentration of 0.2 to
0.4 mg/mL. More concentrated solutions show crystal formation upon stirring or seeding
within 5 minutes and should not be given intravenously.
Note: Hard plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile,
butadiene, and styrene) have been reported to crack and leak when used with UNDILUTED
Hypotension following rapid intravenous administration has been reported, hence, the diluted
Etoposide Injection solution should be administered over a period of 30 to 60 minutes.
More prolonged infusion lessens the risk of a hypotensive reaction.
Etoposide should not be mixed with other antineoplastic agents in the infusion solution.
Contact with buffered aqueous solutions above pH 8 should be avoided. Parenteral drug
products should be inspected visually for particulate matter and discolouration prior to
It is important to ascertain that the intravenous catheter is properly positioned during
etoposide infusion since extravasation of the drug may cause local irritation.
Etoposide Injection solution should be administered immediately after reconstitution,
and certainly within 24 hours, in order to reduce microbiological hazard. DBL
Injection solution should be stored at room temperature and does not need to be protected
from normal room fluorescent light.
Etoposide Injection contains no antimicrobial agent. Use once only and discard any
Specific paediatric dosages have not been evaluated.
As for Adults. However see Dose: With Impaired Liver Function and With Impaired Renal
With Impaired Liver Function :
Page 3 of 11
There are indications that patients with severely impaired liver function (as expressed by an
elevation of serum bilirubin above 85 micromoles/L and clinical jaundice) may develop more
profound myelotoxicity during etoposide treatment. Its use is contraindicated in patients with
severe hepatic dysfunction, and it should be used with caution in patients with mild to
moderate hepatic impairment.
With Impaired Renal Function :
unchanged in urine, dosage adjustment may be necessary in patients with impaired renal
Etoposide should not be mixed with other anti neoplastic agents in the infusion
pH range of maximum stability: Contact with buffered aqueous solutions above pH 8
should be avoided.
Special warnings: The stability of the 1:50 dilutions of etoposide in 0.9% sodium
chloride is 4 hours. If there is any evidence of crystal formation this dilution should
not be administered.
Instructions to be Given to Patient :
The patient should be warned that nausea and reversible alopecia may occur as a result of
The patient should advise the clinician if any symptoms of acute reaction develop during
Etoposide Injection infusion.
Patients should be advised to use adequate contraceptive measures during treatment with
etoposide (see section 4.4).
Patients with severe hepatic dysfunction. Patients who have a demonstrated hypersensitivity
to any of the ingredients. Severe bone marrow failure (WBC less than 2000 cells/mm
platelet count less than 75 000 cells/mm
) not due to malignant disease.
4.4 Special warnings and precautions for use
Etoposide Injection should be administered under the supervision of a qualified physician
experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with
resulting infection or bleeding may occur.
In all instances where the use of Etoposide Injection 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
Page 4 of 11
measures should be taken according to the clinical judgement of the physician. Reinstitution
Injection therapy should be carried out with caution, and with adequate
consideration of the further need for the drug and alertness as to the possible recurrence of
Patients being treated with Etoposide Injection must be observed for myelosuppression
suppression is the most significant toxicity associated with Etoposide Injection therapy.
Therefore the following counts should be obtained at the start of therapy and prior to each
subsequent course of Etoposide Injection: platelet count, haemoglobin, white blood cell count
and differential. The occurrence of a platelet count below 50,000/mm
indicates that the
patient is at risk of bleeding; the occurrence of a total white cell count below 3,000/mm
absolute neutrophil count below 500/mm
indicates that the patient is at risk of infection.
Therapy should not be commenced if there is a risk of the platelet count, the white cell count
or the neutrophil count falling below these levels. Furthermore, if the counts drops below
these levels during therapy, further therapy should be withheld until the blood counts have
Physicians should be aware of the possible occurrence of an anaphylactic reaction manifest
followed by the administration of pressor agents, corticosteroids, antihistamines, or volume
expanders at the discretion of the physician.
There have been reports of cardiac arrest secondary to allergic reactions during infusion with
Etoposide Injection 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
Infections must be brought under control before using etoposide due to bone marrow
suppression following use of the drug and the risk of septicaemia.
Combined chemotherapy may cause increased bone marrow suppression and should be used
Laboratory Tests: Periodic complete blood counts, hepatic and renal function tests and
serum urate should be done during the course of Etoposide Injection treatment. They should
be performed prior to therapy and at appropriate periods during therapy. At least one
determination should be done to each course of Etoposide Injection.
Patients with Impaired Liver or Renal Function : Etoposide Injection should be given
cautiously to individuals with any degree of hepatic or renal dysfunction (see section 4.4).
Safety and effectiveness in children have not been established.
Etoposide Injection contains polysorbate 80. In premature infants a life threatening syndrome
consisting of liver and renal failure, pulmonary deterioration, thrombocytopenia and ascites
has been associated with an injectable Vitamin E product containing polysorbate 80.
Page 5 of 11
4.5 Interaction with other medicines and other forms of interaction
Single case reports exist of increased bone marrow depression and possible increased risk of
anthracycline-induced cardiomyopathy. Etoposide Injection may need to be used with caution
in combination chemotherapy.
4.6 Fertility, pregnancy and lactation
No data available.
Category D. Etoposide Injection can cause foetal harm when administered to pregnant
women. Etoposide Injection had been shown to be teratogenic in mice and rats. There are no
pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be
appraised of the potential hazard to the foetus. Women of childbearing potential should be
advised to avoid becoming pregnant.
Etoposide Injection was subjected to a teratology study in SPF rats at doses of 0.13, 0.4, 1.2
and 3.6 mg/kg/day administered intravenously on Days 6 to 15 of gestation. Etoposide
Injection caused a dose-related maternal toxicity, embryotoxicity and teratogenicity at dose
levels of 0.13 mg/kg/day and higher administered intravenously. Embryonic resorptions were
90 and 100 percent at the two highest dosages. At 0.4 and 1.2 mg/kg, foetal weights were
exencephaly and encephalocoele and anophthalmia.
Even at the lowest dose tested, 0.13 mg/kg, a significant increase in retarded ossification was
A study in Swiss-Albino mice given a single intraperitoneal injection of Etoposide Injection
at dosages of 1.0, 1.5 and 2.0 mg/kg on Days 6, 7 and 8 of gestation showed dose-related
embryotoxicity, various cranial abnormalities and major skeletal malformations.
Australian categorisation definition of Category D: Drugs which have caused, are suspected
to have caused or may be expected to cause, an increased incidence of human foetal
malformations or irreversible damage. These drugs may also have adverse pharmacological
effects. Accompanying text above should be consulted for further details.
It is not known whether this drug is excreted in breast milk. Because many drugs are excreted
in human milk and because of the potential for serious adverse reactions in nursing infants
from Etoposide Injection, 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.
4.7 Effects on ability to drive and use machinery
No data available.
Page 6 of 11
4.8 Undesirable effects
The incidences of adverse reactions, given below as mean percent, are derived from studies
that used single agent Etoposide Injection therapy.
More Common Reactions:
Haematological Toxicity : The principal toxicity of etoposide is dose-related bone marrow
suppression, with granulocyte nadirs occurring 7 to 14 days, and platelet nadirs 9 to 16 days,
after drug administration. Bone marrow recovery is usually complete by day 20, and no
cumulative toxicity has been reported. Leucopenia (less than 4,000 cells/mm
) and severe
leucopenia (less than 1,000 cells/mm
) were observed in 60 to 91 percent and 7 to 17 percent,
respectively, of patients treated with single agent Etoposide Injection. Thrombocytopenia
) were seen in 28 to 41 percent and 4 to 20 percent of this same group of
patients. Pancytopenia was found in 7% of 340 patients treated with 50-60 mg/m
Injection I.V. for 5 days.
The occurrence of acute non-lymphocytic leukaemia with or without preleukaemic phase has
antineoplastic agents, in particular, cisplatin.
Alopecia : Reversible alopecia, sometimes progressing to total baldness, has been observed
in up to 66 percent of patients.
Gastrointestinal Toxicity: Nausea and vomiting are the major gastrointestinal toxicities.
They have been noted in 31-43 percent of patients given intravenous Etoposide Injection. The
nausea and vomiting can usually be controlled by anti-emetic therapy. Anorexia was seen in
10 to 13 percent of patients and stomatitis in 1-6 percent of those patients given intravenous
Etoposide Injection. Diarrhoea was noted in 1 to 13 percent of these patients.
Hypotension : Temporary hypotension following rapid intravenous administration has been
reported. The incidence has been reported between 1 and 2 percent and has not been
associated with cardiac toxicity or electrocardiographic changes. No delayed hypotension has
been noted. To prevent this rare occurrence, it is recommended that Etoposide Injection be
administered by slow intravenous infusion over a 30 to 60 minute period.
If hypotension occurs, it usually responds to stopping the infusion and administering fluids or
other supportive therapy as appropriate. When restarting the infusion, a slower administration
rate should be used.
Less Common Reactions :
Allergic Reactions: Anaphylactic-like reactions characterised by chills, fever, tachycardia,
bronchospasm, dyspnoea and hypotension have also been reported to occur in 0.7 to 2 percent
administration. Anaphylactic-like reactions have occurred very rarely in patients treated with
oral capsules. These reactions have usually responded promptly to the cessation of the
infusion and administration of pressor agents, corticosteroids, antihistamines or volume
expanders as appropriate. One fatal acute reaction associated with bronchospasm has been
Page 7 of 11
normalises with a few hours after cessation of the infusion. Anaphylactic-like reactions can
occur with the initial dose of Etoposide Injection. Apnoea has occurred in patients receiving
Solutions more concentrated than those recommended (see section 4.2) should not be
given intravenously. If such solutions are justifiable, higher rates of anaphylactic-like
reactions may occur.
neuropathy in 0.7 percent of patients. The associated use of vincristine sulphate can possibly
enhance this neuropathy. Caution should be taken when giving etoposide and vincristine
combined to older individuals whose performance status is impaired and to patients with pre-
existing neurological disease and poor nutritional status.
Other Toxicities: The following reactions have been rarely reported:
Central nervous system toxicity (somnolence and fatigue), liver toxicity (transient jaundice
abdominal pain, urticaria, constipation, dysphagia, transient cortical blindness, mucositis,
esophagitis and a single report of
radiation recall dermatitis. One
case of myocardial
infarction has been reported in a patient also treated with mediastinal radiation. There is one
case report of a possible drug-related life-threatening cardiotoxicity. Cardiac arrest and heart
failure, with some fatal outcomes have been reported. Patients with cardiac arrest secondary
to acute allergic reactions recovered completely from their episodes.
Occasionally, following extravasation, soft tissue irritation and inflammation has occurred;
ulceration is generally not seen.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
No information is available relating to etoposide poisoning in humans. No proven antidotes
supportive. Haematologic and gastrointestinal toxic effects are expected to be the principal
manifestations of etoposide overdosage.
For advice on the management of overdose please contact the National Poisons Centre on
0800 POISON (0800 764766).
Page 8 of 11
5.1 Pharmacodynamic properties
Etoposide is a semi-synthetic derivative of podophyllotoxin.
Empirical formula: C
MW: = 588.58
Mechanism of action
In vitro studies suggest that etoposide initially causes metaphase, however this effect appears
to be superseded by interference with cell cycle progression before the cell enters mitosis.
Cytofluorometric studies using human lymphoblast cell lines have shown that the major delay
in cell cycle progression and the maximum cell killing occurs in the S or G2 phases of the
cell cycle. This has been confirmed in several cell lines. The mechanism by which this occurs
is unknown but may be related to an inhibition of nucleoside transport demonstrated in HeLa
cells. Etoposide does not interfere with microtubule assembly. It is particularly active in
human leukaemia cells and a high response rate is also seen in small cell carcinoma of the
Etoposide acts indirectly on cultured HeLa cells and induces single-stranded breaks in DNA.
This effect was not demonstrated on DNA in vitro.
5.2 Pharmacokinetic properties
Absorption from the oral route of administration is variable and incomplete. Peak blood
levels occur about one hour after oral administration.
While the absolute bioavailability averaged approximately 55.0% there were considerable
variations between subjects (17-74%) and in one study within individual subjects.
The standard oral dose is approximately twice the effective intravenous dose.
Following intravenous administration of 100 mg etoposide the peak plasma concentration
ranged from 2.2-6.1 microgram/mL with an average of 4.7, and time to peak ranged from 0.5-
2.0 hours (average 1 hour). Only small levels are found in the cerebrospinal fluid, compared
with plasma levels. In a limited number of children, etoposide administered in a dose of 200-
produced a mean plasma clearance of 17.8±11.2 (SD) mL/min/m
based on a
model-independent method. The elimination half-life based on a model-dependent method
averaged 5.8±3.2 hours.
Page 9 of 11
Etoposide is stored extensively in the tissues and has a volume of distribution during terminal
phase of excretion of 28 L.
Protein binding : In vitro, etoposide is highly protein bound (97%) to human plasma
Etoposide is approximately 66% metabolised. One metabolite has been identified but its
activity not studied. However, it appears to be extensively distributed and retained. After 72
hours, 44% of the administered dose of etoposide was recovered in the urine; 29% as
unchanged drug and 15% as metabolite. Recovery in the faeces ranged from less than 2% to
16% over three days.
Renal clearance 13.6±4.5 mL/min: total body clearance 47±22 mL/min. The one metabolite
identified has a renal clearance of 31.3 mL/min and total clearance of 111.7 mL/min.
Half Life: Etoposide shows a biexponential plasma decay curve. The beta phase half life is
Clinical Implications of Pharmacokinetic Data : Etoposide and its metabolite are widely
distributed within the body and bound to tissue protein. Only about 60% of the administered
drug can be accounted for by unchanged or metabolised drug excreted in the urine or faeces,
indicating prolonged tissue storage.
The fact that approximately 30% of the administered dose is excreted unchanged by the
kidneys indicates that the dosage may need to be adjusted in patients with renal impairment.
5.3 Preclinical safety data
No data available.
Six-month chronic studies in rats have shown Etoposide Injection to have oncogenetic
potential but two-year carcinogenicity tests with Etoposide Injection have not been conducted
in laboratory animals. Given its mechanism of action, it should be considered a possible
carcinogen in humans.
Reproductive and developmental toxicity
Etoposide Injection induced aberrations in chromosome number and structure in embryonic
murine cells. (see also section 4.8)
Page 10 of 11
6.1 List of excipients
No data available.
6.3 Shelf life
24 months from date of manufacture.
6.4 Special precautions for storage
Injection: Store below 25°C. Protect from light.
6.5 Nature and contents of container
Each vial contains 100 mg etoposide in 5 mL solution. DBL
Etoposide Injection is supplied
in packs of one vial.
6.6 Special precautions for disposal and other handling
Procedures for proper handling and disposal of anticancer drugs should be considered.
Several guidelines on this subject have been published, and should be used appropriately.
particular care to prevent spillage and self-contact with the drug. Any solution on the skin
should be vigorously washed off with soap and cold water. Material used for cleaning
accidental spills should be disposed of by incineration.
Any unused medicine or waste material should be disposed of in accordance with local
Pfizer New Zealand Limited