Consumer medicine information

Etoposide Ebewe

Etoposide

BRAND INFORMATION

Brand name

Etoposide Ebewe

Active ingredient

Etoposide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Etoposide Ebewe.

What is in this leaflet

This leaflet answers some common questions about Etoposide Ebewe. It does not contain all the available information.

It does not take the place of talking to your doctor and pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given Etoposide Ebewe against the benefits they expect it will have for you.

This medicine is likely to be used while you are in hospital. If possible, please read this leaflet carefully before this medicine is given to you. In some cases this leaflet may be given to you after the medicine has been used.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet in a safe place. You may need to read it again.

What is Etoposide Ebewe used for

Etoposide belongs to a group of medicines known as antineoplastic or cytotoxic agents. You may also hear it referred to as a chemotherapy medicine.

It is used to treat lung cancer, leukaemia (blood cancer) and cancer of the lymph glands. It interferes with the development of cells and causes cell death, particularly in cancer cells.

Etoposide Ebewe may be used alone or in combination with other medicines to treat cancer.

Your doctor may have prescribed Etoposide Ebewe for another reason. Ask your doctor if you have any questions about why Etoposide Ebewe has been prescribed for you.

This medicine is available only with a doctor's prescription.

Before you are given Etoposide Ebewe

When you must not be given it

Etoposide Ebewe should not be given to you if you have an allergy to etoposide or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction to etoposide may include:

  • chills/fever
  • fast heart beat
  • shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • dizziness or light headedness
  • flushing, sweating

Etoposide Ebewe should not be given to you if you have, or have had any of the following medical conditions, unless you have discussed it with your doctor:

  • you have bone marrow suppression (decreased blood cell production)
  • you have severe liver or renal disease
  • a blood disorder with a reduced number of white blood cells
  • a blood disorder in which there is a decreased number of red blood cells
  • a blood disorder with a low blood platelet count

Etoposide Ebewe should not be given with concomitant use of yellow fever vaccine or other live vaccines in immunocompromised patients.

Etoposide Ebewe should not be given to you if you have had recent surgery.

Etoposide Ebewe should not be given to you if you are receiving radiation therapy or any other medicines which lower your immune system.

Etoposide Ebewe should not be given to you if you are pregnant or intend to become pregnant and if you are breast feeding. Like most medicines used to treat cancer, Etoposide Ebewe is not recommended for use during pregnancy and lactation, unless you and your doctor have discussed the risks and benefits involved.

You and your partner must use a reliable method of contraception (birth control) during treatment with Etoposide Ebewe and for at least 6 months after you stop using it. This medicine may cause birth defects if either the male or female is receiving it at the time of conception or if it is used during pregnancy.

In addition, many cancer medicines can cause infertility. Your doctor should discuss this issue with you before you begin therapy with etoposide.

Do not breastfeed while you are on treatment with Etoposide Ebewe, unless you have discussed it with your doctor. Etoposide Ebewe passes into human breast milk. As Etoposide Ebewe may cause serious side effects in a breast fed baby, breast feeding is not recommended while you are receiving it.

Before you are given it

Tell your doctor or pharmacist if you have allergies to:

  • etoposide
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.

Tell your doctor or pharmacist if you have or have had any medical conditions, especially the following:

  • kidney or liver disease
  • infection or high temperature

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

If you have not told your doctor about any of the above, tell them before you are given Etoposide Ebewe.

Your doctor may decide to delay your treatment until the infection has gone. A mild illness, such as a cold is not usually a reason to delay treatment.

Taking other medicines

Tell your doctor or pharmacist if you are taking/using any other medicines, including medicines that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and etoposide may interfere with each other. This includes:

  • levamisol (ergamisol) - a
  • medicine that is used to treat some other forms of cancer
  • ciclosporin - a medicine used to prevent rejection of transplanted organs
  • cisplatin
  • anti-epileptics
  • warfarin
  • any medicines which suppress your immune system.

These medicines may be affected by Etoposide Ebewe, or affect how well it works. You may need different amounts of your medicine, or you may need to have different medicines. Your doctor will advise you.

While you are being treated with etoposide, and for about one month after you stop treatment with it, do not have any immunisations (vaccinations) without your doctor's approval. Etoposide may lower your body's resistance and there is a chance you may get the infection the immunisation is meant to prevent. In addition, other persons living in your household should not take oral polio vaccine (sabin) since there is a chance they could pass the polio virus on to you.

Your doctor may have more information on medicines to be careful with or avoid while taking Etoposide Ebewe.

If you have not told your doctor about any of the above, tell them before you start Etoposide Ebewe. If you are not sure whether you should be given Etoposide Ebewe, talk to your doctor.

How Etoposide Ebewe is given

How much is given

Your doctor will decide what dose of etoposide you will receive.

Your dose of Etoposide Ebewe is worked out based on your body weight and height and on the type of cancer you have. The dose worked out for you may be different to the dose of another patient.

Etoposide Ebewe may be given alone or in combination with other anti-cancer drugs.

Several courses of Etoposide Ebewe therapy may be needed depending on your response to treatment.

Additional treatment may not be repeated until your blood cell numbers return to acceptable levels and any uncontrolled effects have been controlled.

Ask your doctor if you want to know more about the dose of Etoposide Ebewe you receive.

How it is given

Etoposide Ebewe should only be prepared, administered and monitored by a doctor or nurse.

Etoposide Ebewe is given as an intravenous infusion (ie. a slow injection via a "drip" into a vein).

How long is it given

Etoposide Ebewe is usually given each day for 5 days. This is followed by a treatment-free interval of 2-4 weeks. This is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need.

If you are given too much (overdose)

As your dose of Etoposide Ebewe will be determined and administered by a medical specialist the chance of receiving an overdose is most unlikely. However, if an overdose is given, your specialist will give you the appropriate treatment.

If you experience severe side effects tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital.

Symptoms of an etoposide overdose include the side effects listed below in the 'Side Effects' section, but are usually of a more severe nature. These may include, kidney failure, liver failure, failure of the immune system and inflammation and ulceration of the mouth and stomach.

While you are being given Etoposide Ebewe

Tell your doctor, nurse or pharmacist if you have any concerns before, during or after administration of Etoposide Ebewe.

Etoposide Ebewe is known to be powerful at reducing the body's ability to make blood cells. Therefore, regular blood tests will be required.

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

Things you must do

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor may want to check your blood pressure and do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow up appointments with your doctor. It is important to have your follow-up infusions of Etoposide Ebewe at the appropriate time to get the best effect from your treatments.

If you forget an appointment, contact your doctor immediately.

Tell any other doctors, dentists and pharmacists who are treating you that you are being given Etoposide Ebewe.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are undergoing therapy with Etoposide Ebewe.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are undergoing therapy with Etoposide Ebewe.

If you become pregnant or are breastfeeding while undergoing therapy with Etoposide Ebewe, tell your doctor.

Etoposide can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding. The following should be taken to reduce your risk of infection or bleeding:

  • Avoid people who have infections. Check with your doctor immediately if you think you may be getting an infection, or if you get a fever, chills, cough, hoarse throat, lower back or side pain, or find it painful or difficult to urinate;
  • Be careful when using a regular toothbrush, dental floss or toothpick. Your doctor, dentist, pharmacist or nurse may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work done;
  • Be careful not to cut yourself when you are using sharp objects such as a razor or nail cutters;
  • Avoid contact sports or other situations where you may bruise or get injured.

Things you must not do

Do not drink alcohol while taking Etoposide Ebewe. You may feel flushed or get headaches.

Things to be careful of

Be careful when driving or operating machinery until you know how Etoposide Ebewe affects you. As with other medicines used to treat cancer, Etoposide Ebewe may cause dizziness, light-headedness or tiredness in some people. Make sure you know how you react to Etoposide Ebewe before you drive a car, operate machinery, or do anything else that could be dangerous if you are dizzy or light-headed. If this occurs do not drive. If you drink alcohol, dizziness or light-headedness may be worse.

Side effects

Tell your doctor, nurse or pharmacist as soon as possible if you do not feel well while you are being given Etoposide Ebewe, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like other medicines that treat cancer, etoposide may have unwanted side effects, some of which may be serious. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

These are the more common side effects of Etoposide Ebewe

  • nausea, vomiting, diarrhoea
  • loss of appetite
  • soreness or ulceration of the mouth
  • stomach pain, constipation, altered taste
  • unusual hair loss or thinning
  • dizziness, light-headedness
  • feeling tired or weak
  • problems swallowing
  • low/high blood pressure
  • pigmentation, rash, prutitus, urticaria

Tell your doctor or nurse as soon as possible if you notice any of the following:

These may be serious side effects. You may need medical attention.

  • frequent infections such as fever, severe chills, sore throat and mouth ulcers
  • bleeding or bruising more easily than normal, nose bleeds, rash of small reddish-purple spots on your skin, blood in your stool or urine
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale, fast heart rate
  • numbness, tingling and pain in hands or feet
  • itching of the skin, joint aches, blisters that look like hives on the upper body, legs, arms, palms, hands, or feet and may involve the face or lips,
  • yellowing of the skin or whites of the eyes
  • abdominal pain
  • abnormal physical weakness or lack of energy
  • sore mouth, eye pain, vision problems
  • burning, stinging, pain, redness or swelling at the injection site
  • kidney problems mainly in children when high doses are given which is usually reversible.

Tell your doctor immediately or go to the Accident and Emergency department of your nearest hospital if you notice any of the following signs of a sudden life-threatening allergic reaction:

  • fast heartbeat, chills and fever; shortness of breath, wheezing, coughing or difficulty breathing; dizziness, flushing, sweating, swelling of the face, lips, tongue or other parts of the body, itching or hives on the skin.

Treatment with etoposide may cause changes in your blood cells which may be serious. Etoposide may also affect how your kidneys and liver work. Your doctor will arrange regular blood tests and checks to detect any changes.

Some people may get other side effects while being given etoposide.

Tell your doctor, nurse or pharmacist if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After being given Etoposide Ebewe

The benefits and side effects of Etoposide Ebewe may take some time to occur. Therefore even after you have finished your Etoposide Ebewe treatment you should tell your doctor immediately if you notice any of the side effects listed in the previous section.

Storage

Etoposide Ebewe will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place where the temperature stays below 25°C. Protect from light.

After use, any unused portion of the vial will be discarded.

Product description

What it looks like

Etoposide Ebewe is a clear, colourless to yellow liquid contained in a clear glass vial.

Etoposide Ebewe is available in:

  • 50 mg of etoposide per 2.5 mL vial, 1's
  • 100 mg of etoposide per 5 mL vial, 1's and 5's
  • 200 mg of etoposide per 10 mL vial, 1's
  • 400 mg of etoposide per 20 mL vial, 1's
  • 1000 mg of etoposide per 50 mL vial, 1's

Not all strengths may be marketed in Australia.

Ingredients

Active ingredient:

  • etoposide

Other ingredients:

  • citric acid
  • macrogol 300
  • ethanol
  • polysorbate 80
  • benzyl alcohol

Etoposide Ebewe does not contain gluten, lactose, sucrose, tartrazine or any other azo dyes.

Manufacturer

Ebewe Pharmaceuticals Ltd
A-4866
Unterach
Austria, Europe

Distributor

Sandoz Pty Ltd
54 Waterloo Road
Macquarie Park, NSW 2113
Australia
Tel: 1800 726 369

Australian Registration Numbers

50 mg injection: AUST R 96636 (vial)

100 mg injection: AUST R 96641 (vial)

200 mg injection: AUST R 96642 (vial)

400 mg injection: AUST R 96643 (vial)

1000 mg injection: AUST R 96644 (vial)

This leaflet was revised in April 2020.

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Etoposide Ebewe

Active ingredient

Etoposide

Schedule

S4

 

1 Name of Medicine

Etoposide.

2 Qualitative and Quantitative Composition

Etoposide is a semi-synthetic derivative of podophyllotoxin. It appears as a white or almost white, crystalline powder, soluble in methanol and chloroform, slightly soluble in ethanol and sparingly soluble in water and ether. It is more miscible with water by means of organic solvents.
Active: etoposide (20 mg/mL).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Etoposide Ebewe is concentrated injection.

4 Clinical Particulars

4.1 Therapeutic Indications

Etoposide Ebewe concentrated injection (etoposide) is indicated for use in the treatment of:
1. Small cell carcinoma of the lung.
2. Acute monocytic and myelomonocytic leukaemia.
3. Hodgkin's disease.
4. Non-Hodgkin's lymphoma.

4.2 Dose and Method of Administration

Dosage.

Adults.

Administer intravenously, 50 to 60 mg/m2/day for five days followed by a treatment free interval of two to four weeks.
Total dose should not exceed 400 mg/m2 per course.

Method of administration.

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 Etoposide Ebewe concentrated injection.
Etoposide Ebewe is nonaqueous.
Etoposide Ebewe must be diluted prior to use with either sodium chloride 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 five minutes and should not be given intravenously. Hypotension following rapid intravenous administration has been reported, hence, the diluted etoposide solution should be administered over a period of 30 to 60 minutes. More prolonged infusion lessens the risk of a hypotensive reaction.
Etoposide Ebewe should not be administered by intrapleural or intraperitoneal injection.
Biological activity appears to be schedule dependent with multiple dosages over three to five days showing superiority over single dose administration.
Etoposide Ebewe must be diluted prior to use with either sodium chloride 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 five minutes and should not be given intravenously.
Etoposide Ebewe should not be given by a rapid intravenous push.
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 medicine products should be inspected visually for particulate matter and discolouration prior to administration.
It is important to ascertain that the intravenous catheter is properly positioned during etoposide infusion since extravasation of the medicine may cause local irritation.
The use of Pharmacy Bulk Pack should be restricted to suitably qualified pharmacists operating in suitably equipped hospital pharmacies or compounding centres. The Pharmacy Bulk Pack is intended for multiple dispensing into sterile solutions for subsequent infusion in individual patients in one treatment session. The Pharmacy Bulk Pack should be spiked only once. To reduce microbiological hazard, admixtured solutions should be used as soon as practicable after preparation. If storage is required, hold at 2 to 8°C for no more than 24 hours.

Dosage adjustment.

Renal impairment.

Since some etoposide (about 30% of an intravenously administered dose) is excreted unchanged in urine, dosage adjustment may be necessary in patients with impaired renal function.
The following initial dose modification should be considered based on measured creatinine clearance (see Table 1).
Subsequent dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearance < 15 mL/min and further dose reduction should be considered in those patients.

Hepatic impairment.

There are indications that patients with severely impaired liver function (as expressed by an elevation of serum bilirubin above 85 micromol/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.

Paediatrics.

Specific paediatric dosages have not been evaluated.

Elderly.

As for adults. However, see Renal impairment and Hepatic impairment above.

4.3 Contraindications

Etoposide is contraindicated:
in patients with severe hepatic or renal dysfunction;
in those patients who have demonstrated a previous hypersensitivity to etoposide or any component of the formulation;
in severe bone marrow failure (WBC less than 2,000 cells/mm3 or platelet count less than 75,000 cells/mm3) not due to malignant disease;
with concomitant use of yellow fever vaccine or other live vaccines in immunocompromised patients;
in lactation.
Etoposide must not be given by intra-cavity injection.

4.4 Special Warnings and Precautions for Use

Etoposide should be administered and monitored under the supervision of a qualified doctor experienced in the use of cancer chemotherapeutic agents. Severe myelosuppression with resulting infection or bleeding may occur.

General.

In all instances where the use of etoposide is considered for chemotherapy, the doctor must evaluate the need and usefulness of the medicine against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the medicine should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the doctor. Reinstitution of etoposide therapy should be carried out with caution, and with adequate consideration of the further need for the medicine and alertness as to the possible recurrence of toxicity.
Patients with low serum albumin may be at increased risk for etoposide associated toxicities.

Myelosuppression.

Fatal myelosuppression has been reported following etoposide administration.
Patients being treated with etoposide must be observed for myelosuppression carefully and frequently both during and after therapy. Dose limiting bone marrow suppression is the most significant toxicity associated with etoposide therapy. After administration according to a 'daily for five days' schedule, the nadir is reached within two to three weeks after the start of treatment and bone marrow recovery occurs within three weeks. The lowest level of thrombocytopenia occurs within a few days of starting therapy.
Therefore, the following counts should be obtained at the start of therapy and prior to each subsequent course of etoposide: platelet count, haemoglobin, white blood cell count and differential. The occurrence of a platelet count below 50,000/mm3 indicates that the patient is at risk of bleeding; the occurrence of a total white cell count below 3,000/mm3 or an absolute neutrophil count below 500/mm3 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 drop below these levels during therapy, further therapy should be withheld until the blood counts have sufficiently recovered.
Dosage should be modified to take into account the myelosuppressive effects of other medicines in the combination or the effects of prior X-ray therapy or chemotherapy which may have compromised bone marrow reserves.
Infections must be brought under control before using etoposide due to bone marrow suppression following use of the medicine and the risk of septicaemia.
Combined chemotherapy may cause increased bone marrow suppression and should be used with caution.

Tumour lysis syndrome.

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

Anaphylactic reactions.

Doctors should be aware of the possible occurrence of an anaphylactic reaction manifest by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic. Administration of etoposide should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the doctor.
There have been reports of cardiac arrest secondary to allergic reactions during infusion with etoposide.
Injection site reactions may occur during the administration of etoposide (see Section 4.8 Adverse Effects (Undesirable Effects)). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.
Etoposide should be given only by slow intravenous infusion (usually over a 30 to 60 minute period) since hypotension has been reported as a possible side effect of rapid intravenous infusion.

Instructions to patients.

The patient should be warned that nausea and reversible alopecia may occur as a result of etoposide therapy. The patient should advise the clinician if any symptoms of acute reaction develop during etoposide infusion. Patients should be advised to use adequate contraceptive measures during treatment with etoposide (see Section 4.4 Special Warnings and Precautions for Use).

Vaccinations.

Concomitant use of etoposide with a live virus vaccine may potentiate the replication of the vaccine virus and/or may increase the adverse reaction of the vaccine virus because normal defense mechanisms may be suppressed by etoposide. Vaccination with a live vaccine in a patient taking etoposide may result in severe infection. Patient's antibody response to vaccines may be decreased. The use of live vaccines should be avoided and individual specialist advice sought (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Other interactions).

Use in hepatic impairment.

Etoposide should be given cautiously to individuals with any degree of hepatic dysfunction (see Section 4.2 Dose and Method of Administration, Hepatic impairment). Patients with severely impaired liver function (as expressed by an elevation of serum bilirubin above 85 micromole/L and clinical jaundice) may develop more profound myelotoxicity during treatment (see Section 4.3 Contraindications).

Use in renal impairment.

Etoposide should be given cautiously to individuals with any degree of renal dysfunction (see Section 4.2 Dose and Method of Administration, Renal impairment). Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and lower steady-state volume of distribution. In one study, clearance was reduced by 30% in patients with serum creatinine > 130 micromole/L compared with patients with serum creatinine < 100 micromole/L.
Reversible acute renal failure have been reported with administration of high dose (2220 mg/m2) etoposide phosphate with total body irradiation used for hematopoietic stem cell transplantation. Renal function should be evaluated prior to and after etoposide phosphate administration until complete renal function recovery. (See Section 4.8 Adverse Effects (Undesirable Effects)).

Use in the elderly.

Clinical studies of etoposide for the treatment of refractory testicular tumours did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Of more than 600 patients in four clinical studies in the NDA databases who received etoposide or etoposide phosphate in combination with other chemotherapeutic agents for the treatment of small cell lung cancer (SCLC), about one third were older than 65 years. When advanced age was determined to be a prognostic factor for response or survival in these studies, comparison between treatment groups were performed for the elderly subset. In the one study (etoposide in combination with cyclophosphamide and vincristine and doxorubicin) where age was a significant prognostic factor for survival, a survival benefit for elderly patients was observed for the etoposide regimen compared with the control regimens. No differences in myelosuppression were seen between elderly and younger patients in these studies except for an increased frequency of WHO grade III or IV leucopenia among elderly patients in a study of etoposide phosphate or etoposide in combination with cisplatin. Elderly patients in this study also had more anorexia, mucositis, dehydration, somnolence and elevated BUN levels than younger patients.
In five single agent studies of etoposide phosphate in patients with a variety of tumour types, 34% of patients were aged 65 years or more. WHO grade III or IV leucopenia, granulocytopenia, and asthenia were more frequent among elderly patients. Postmarketing experience also suggests the elderly patients may be more sensitive to some of the known adverse effects of etoposide including myelosuppression, gastrointestinal effects, infectious complication and alopecia.
Although some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed these differences were not considered clinically significant. Etoposide and its metabolites are known to be substantially excreted by the kidney and the risk of adverse reactions to this medicine may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Section 4.2 Dose and Method of Administration, Renal impairment for recommended dosing adjustment in patients with renal impairments).

Paediatric use.

Safety and effectiveness in children have not been systematically established.
Etoposide contains polysorbate 80. In premature infants a life threatening syndrome consisting of renal and hepatic failure, pulmonary deterioration, thrombocytopenia and ascites has been associated with an injectable vitamin E product containing polysorbate 80.

Effects on laboratory tests.

Periodic complete blood counts, hepatic and renal function tests and serum urate should be done during the course of etoposide 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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Etoposide should not be physically mixed with any other drug.
Etoposide may need to be used with caution in combination chemotherapy.
Caution should be exercised when administering etoposide with drugs that are known to inhibit phosphatase activities (e.g. levamisole hydrochloride). High dose ciclosporin, resulting in concentrations above 2,000 nanogram/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 antiepileptic therapy may be associated with increased etoposide clearance and reduced efficacy.
Co-administration of antiepileptic drugs and etoposide can lead to decreased seizure control due to pharmacokinetic interactions between the drugs.
Concomitant warfarin therapy may result in elevated international normalized ratio (INR). Close monitoring of INR is recommended.

Other interactions.

Cross resistance between anthracyclines and etoposide has been reported in preclinical experiments. Single case reports exist of increased bone marrow depression and possible increased risk of anthracycline induced cardiomyopathy.
There is increased risk of fatal systemic vaccine disease with the concomitant use of live vaccines. Live vaccines are not recommended in immunosuppressed patients (see Section 4.4 Special Warnings and Precautions for Use, Vaccinations).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Etoposide induced aberrations in chromosome number and structure in embryonic murine cells (see Section 4.8 Adverse Effects (Undesirable Effects)).
Studies with male animals indicate that etoposide treatment causes irreversible atrophy of the testes with accompanying spermatogenesis defects in the testes and epididymis, and reduced seminal vesicle and prostrate secretions.
(Category D)
Etoposide can cause foetal harm when administered to pregnant women. Etoposide has been shown to be teratogenic in mice and rats, and it is therefore expected that etoposide is also teratogenic. There are no adequate and well controlled studies in pregnant women. Etoposide should not be used during pregnancy unless the clinical condition of the woman requires treatment with etoposide. If this medicine is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be informed of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant.
Etoposide 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 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% at the two highest dosages. At 0.4 and 1.2 mg/kg, foetal weights were decreased and foetal abnormalities occurred including major skeletal abnormalities, exencephaly and encephalocele and anophthalmia. Even at the lowest dose tested, 0.13 mg/kg, a significant increase in retarded ossification was observed.
A study in Swiss-Albino mice given a single intraperitoneal injection of etoposide 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.
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.
 Etoposide is excreted in human milk. There is the potential for serious adverse reactions in breastfed infants from etoposide. A decision should be made whether to discontinue breastfeeding or to discontinue the medicine, taking into account the benefit of breast-feeding for the child and the benefit of medicine to the mother.

4.7 Effects on Ability to Drive and Use Machines

Adverse reactions such as fatigue and transient cortical blindness suggest that driving or using machinery is not recommended soon after treatment with etoposide.

4.8 Adverse Effects (Undesirable Effects)

The following data on adverse reactions are based on both oral and intravenous administration of etoposide as a single agent, using several different dose schedules for treatment of a wide variety of malignancies.
Very common > 1/10; Common > 1/100 and < 1/10; Uncommon > 1/1000 and < 1/100; Rare > 1/10,000 and < 1/1000; Very rare < 1/10,000.

Cardiovascular.

Common: Myocardial infarction, arrhythmia.
Rare: Cardiac arrest and heart failure some with fatal outcomes have been reported. Patients with cardiac arrest secondary to acute allergic reactions recovered fully from their episodes.

Vascular.

Common: Hypertension, hypotension including transient systolic hypotension following rapid intravenous administration.
Uncommon: Haemorrhage.

Haematological.

Very common: Leukopenia, neutropenia, thrombocytopenia, anaemia.
Uncommon: Leukaemia (with or without preleukaemic phase in combination therapy), extravasation*/phlebitis.

Gastrointestinal.

Very common: Nausea, vomiting, constipation, mucositis, anorexia, abdominal pain.
Common: Stomatitis, diarrhoea, esophagitis, taste alteration.
Rare: Dysphagia.

Infections and infestations.

Common: Infection.

Metabolism and nutrition disorders.

Unknown: Tumour lysis syndrome.

Neurological.

Very common: Chills and/or Fever.
Common: Dizziness.
Uncommon: Peripheral neuropathy, somnolence, fatigue, seizures (occasionally associated with allergic reactions).

Reproductive system and breast disorders.

Not known: Infertility.

Skin and appendages.

Very common: Alopecia, pigmentation.
Common: Pruritus, rash, urticaria.
Uncommon: Soft tissue irritation and inflammation (following extravasation).
Rare: Radiation recall dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, maculopapular rash.

Hypersensitivity.

Common: Anaphylactic-like reactions (can be fatal) (chills, fever, tachycardia, bronchospasm, dyspnea, hypotension, hypertension, diaphoresis, loss of consciousness, facial flushing, seizures, apnea, rigors, nausea and vomiting), anaphylactic-like reactions (facial/tongue swelling, coughing, cyanosis, tightness in throat, laryngospasm, back pain), Stevens-Johnson syndrome.
Rare: Pruritic erythematous maculopapular rash (consistent with perivasculitis has been reported at investigational doses).
Very rare: Radiation recall dermatitis.
Not known: Angioedema, bronchospasm.

Hepatobiliary.

Very common: Alanine aminotransferase increased, alkaline phosphatase increased, aspartate amino transferase increased, bilirubin increased, hepatotoxicity.
Uncommon: Elevated liver enzymes.

Respiratory.

Rare: Bronchospasm, apnoea, interstitial pneumonitis/pulmonary fibrosis.

Ophthalmological.

Rare: Optic neuritis, transient cortical blindness.

General disorders and administration site conditions.

Very common: Asthenia, malaise.
Common: Extravasation (post-marketing complications reported for extravasation included soft tissue toxicity, swelling, pain, cellulitis, and necrosis including skin necrosis), phlebitis.
Rare: Pyrexia.

Renal and urinary disorders.

Not Known: Acute renal failure.

Neoplasms benign and malignant (including cysts and polyps).

Unknown: Acute leukaemia.
*Post-marketing complications reported for extravasation included local soft tissue toxcitiy, swelling, pain, cellulitis, and necrosis including skin necrosis.
Reversible acute renal failure has been reported in post-marketing experience (see Section 4.4 Special Warnings and Precautions for Use).
The incidence of adverse reactions, given below as a mean percent, are derived from studies that used single agent etoposide therapy.

More common reactions.

Haematological.

Myelosuppression with fatal outcome has been reported following etoposide administration (see Section 4.4 Special Warnings and Precautions for Use). The principal toxicity of etoposide is dose related bone marrow suppression with granulocyte nadir occurring 7 to 14 days, and platelet nadir 9 to 16 days, after medicine administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Leucopenia (< 4,000 cells/mm3) and severe leucopenia (< 1,000 cells/mm3) were observed in 60 to 91% and 7 to 17%, respectively, of patients treated with single agent etoposide. Thrombocytopenia (< 100,000 platelets/mm3) and severe thrombocytopenia (< 50,000 platelets/mm3) were seen in 28 to 41% and 4 to 20% of this same group of patients. Pancytopenia was found in 7% of 340 patients treated with 50 to 60 mg/m2 intravenous etoposide for five days.
The occurrence of acute nonlymphocytic leukaemia with or without preleukaemic phase has been reported in patients treated with etoposide in association with either antineoplastic agents, in particular cisplatin.
Bleeding has been reported.

Alopecia.

Reversible alopecia, sometimes progressing to total baldness, has been observed in up to 66% of patients.

Gastrointestinal.

Nausea and vomiting are the major gastrointestinal toxicities. They have been noted in 31 to 43% of patients given intravenous etoposide. The nausea and vomiting can usually be controlled by antiemetic therapy. Anorexia was seen in 10 to 13% of patients and stomatitis in 1 to 6% of those patients given intravenous etoposide. Diarrhoea was noted in 1 to 13% of these patients.

Cardiovascular.

Temporary hypotension following rapid intravenous administration has been reported. The incidence has been reported between 1 and 2% 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 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.
Cardiac arrest and heart failure, some with fatal outcomes, have been reported. Patients with cardiac arrest secondary to acute allergic reactions recovered fully from their episodes.

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% of patients, occurring during or immediately after intravenous etoposide administration. These reactions have usually responded promptly to the cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate. Diaphoresis, syncope and fatal acute reactions associated with bronchospasm have been reported. Hypertension and/or flushing and/or seizures have also been reported. Blood pressure usually normalises with a few hours after cessation of the infusion. Anaphylactic-like reactions can occur with the initial dose of etoposide. Apnoea has occurred in patients receiving etoposide infusion.
Solutions more concentrated than those recommended (see Section 4.2 Dose and Method of Administration) should not be given intravenously. If such solutions are justifiable, higher rates of anaphylactic-like reactions may occur.

Neuropathy.

The use of etoposide has been reported to cause peripheral neuropathy in 0.7% of patients. The associated use of vincristine sulfate 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.

The following reactions have been rarely reported: central nervous system toxicity (somnolence and fatigue), liver toxicity (transient jaundice and elevated alkaline phosphatase), renal toxicity (elevated urea; hyperuricaemia), septicaemia during high dose regimens, aftertaste, fever, toxic epidermal necrolysis (one fatal case has been reported), constipation, dysphagia, transient cortical blindness 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 medicine related life threatening cardiotoxicity. Ulceration is generally not seen.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Total doses of 2.4 g/m2 to 3.5 g/m2 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 doses of etoposide.
No known antidotes have been established for Etoposide Ebewe. Treatment will be mainly supportive. Haematological and gastrointestinal toxic effects are expected to be the principal manifestations of etoposide overdosage.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

In vitro studies suggest that etoposide initially causes metaphase arrest, 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 and 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. The predominant macromolecular effect of etoposide appears to be DNA synthesis inhibition.
Two different dose dependent responses are seen. At high concentrations (10 microgram/mL or more), lysis of cells entering mitosis is observed. At low concentrations (0.3 to 10 microgram/mL), cells are inhibited from entering prophase.
It is particularly active in human leukaemia cells and a high response rate is also seen in small cell carcinoma of the lung.
Etoposide acts indirectly on cultured HeLa cells and induces single stranded breaks in DNA. This effect was not demonstrated on DNA in vitro.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Following intravenous administration of 100 mg etoposide the peak plasma concentration ranged from 2.2 to 6.1 microgram/mL with an average of 4.7 microgram/mL, and time to peak ranged from 0.5 to 2.0 hours (average one hour).

Distribution.

Following IV administration, etoposide is distributed minimally into pleural fluid and has been detected in the saliva, liver, spleen, kidney, myometrium and brain. It is not known if etoposide is distributed into breast milk. The medicine apparently crosses the placenta in animals. Only small levels are found in the cerebrospinal fluid (CSF) compared with plasma levels. Etoposide concentrations are higher in healthy lung tissue than in lung metastases.
Etoposide is stored extensively in the tissues and has an apparent steady-state volume of distribution of 18 to 29 L or 7 to 17 L/m2 in adults, and 5 to 10 L/m2 in children.

Protein binding.

In vitro, etoposide is highly protein bound to human plasma proteins. Plasma protein binding as determined by the ultra filtration method has been reported to be 74% at a plasma level of 10 microgram/mL and over 90% at a plasma level of 1 microgram/mL (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Metabolism.

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 intravenous administration of 14C-etoposide (100-124 mg/m2), mean recovery of radioactivity in the urine was 56% of the dose at 120 hours, 45% of which was excreted as etoposide; faecal recovery of radioactivity was 44% of the dose at 120 hours.

Excretion.

Renal clearance has been reported to be 13.6 +/- 4.5 mL/minute; total body clearance 47 +/- 22 mL/minute. The one metabolite identified has a renal clearance of 31.3 mL/minute and total clearance of 111.7 mL/minute.
In a limited number of children, etoposide administered in a dose of 200 to 250 mg/m2 produced a mean plasma clearance of 17.8 +/- 11.2 (SD) mL/minute/m2 based on a model independent method. The elimination half-life based on model dependent method averaged 5.8 +/- 3.2 hours.
In children elevated serum SGPT (serum glutamic pyruvic transaminase) levels are associated with reduced medicine total body clearance. An inverse relationship between plasma albumin levels and etoposide renal clearance is found in children.
Biliary excretion of unchanged medicine and/or metabolites is an important route of etoposide elimination as faecal recovery of radioactivity is 44% of the intravenous dose. The hydroxyl acid metabolite [4'-demethylepipodophyllic acid- 9-(4,6-O-(R)-ethylidene-b-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 sulfate conjugates of etoposide are also excreted in human urine. Only 8% or less of an intravenous dose is excreted in the urine as radiolabeled metabolites of 14C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

Half-life.

Etoposide shows a bioexponential plasma decay curve. The beta phase half-life is 11.5 hours.

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 medicine can be accounted for by unchanged or metabolised medicine 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

Genotoxicity.

Based upon its pharmacodynamic mechanism of action, etoposide is a potential genotoxic agent. Etoposide has been shown to be mutagenic in mammalian and bacterial cells and etoposide is expected to have similar mutagenic effects.

Carcinogenicity.

Six-month chronic studies in rats have shown etoposide to have oncogenetic potential but two year carcinogenicity tests with etoposide have not been conducted in laboratory animals. However, based upon its pharmacodynamic mechanism of action, etoposide is a potential carcinogenic agent.
The occurrence of acute leukaemia, which can occur with or without a preleukaemic phase, has been reported rarely in patients treated with etoposide in association with other antineoplastic drugs.

6 Pharmaceutical Particulars

6.1 List of Excipients

Citric acid, macrogol 300, polysorbate 80, ethanol, benzyl alcohol.

6.2 Incompatibilities

Etoposide should not be mixed with other antineoplastic agents in the infusion solution.

pH range of maximum stability.

Contact with buffered aqueous solutions above pH 8 should be avoided.

Special warnings.

The chemical stability of the 1:50 dilutions of etoposide in 0.9% sodium chloride is four hours. If there is any evidence of crystal formation, this dilution should not be administered.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

Etoposide solution for infusion should be administered immediately after reconstitution, and certainly within 24 hours, in order to reduce microbiological hazard.
In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Etoposide solution for infusion should be stored at room temperature.
Store below 25°C.
Protect from light.

6.5 Nature and Contents of Container

Etoposide Ebewe 50 mg/2.5 mL concentrated injection.

Glass vial. Pack of 1 vial.

Etoposide Ebewe 100 mg/5 mL concentrated injection.

Glass vial. Pack of 1 vial and 5 vials.

Etoposide Ebewe 200 mg/10 mL concentrated injection.

Glass vial. Pack of 1 vial (Oncology pharmacy bull pack).

Etoposide Ebewe 400 mg/20 mL concentrated injection.

Glass vial. Pack of 1 vial (Oncology pharmacy bull pack).

Etoposide Ebewe 1000 mg/50 mL concentrated injection.

Glass vial. Pack of 1 vial (Oncology pharmacy bull pack).
Not all presentations may be marketed in Australia.
Vial stopper not made with natural rubber latex.

6.6 Special Precautions for Disposal

Etoposide Ebewe contains no antimicrobial agent. The product is for single use in one patient only. Discard any unused residue.

Procedures for handling and disposal.

Procedures for proper handling and disposal of anticancer medicines should be considered. Several guidelines on this subject have been published, and should be used appropriately. Professional staff administering etoposide infusions should exercise particular care to prevent spillage and self-contact with the medicine. 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.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: 4'-demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-β-D-glucopyranoside].
Molecular formula: C29H32O13.
Molecular weight: 588.58.

CAS number.

33419-42-0.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes