Consumer medicine information

Etopophos

Etoposide

BRAND INFORMATION

Brand name

Etopophos

Active ingredient

Etoposide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Etopophos.

SUMMARY CMI

ETOPOPHOS®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using ETOPOPHOS?

ETOPOPHOS contains the active ingredient etoposide phosphate. ETOPOPHOS is used to treat lung cancer, leukaemia (blood cancer), cancer of the lymph glands and testicular cancer.

For more information, see Section 1. Why am I using ETOPOPHOS? in the full CMI.

2. What should I know before I use ETOPOPHOS?

Do not use if you have ever had an allergic reaction to etoposide phosphate or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ETOPOPHOS? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ETOPOPHOS and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ETOPOPHOS?

  • ETOPOPHOS must only be prepared and administered by a doctor or nurse.
  • ETOPOPHOS injection is given as an infusion (drip) into your veins, over 5 minutes to 3.5 hours.
  • ETOPOPHOS is usually given for 1 to 5 days for lower dose and every other day: days 1,3,5 for higher dose. This is followed by a treatment-free interval of 3-4 weeks.

More instructions can be found in Section 4. How do I use ETOPOPHOS? in the full CMI.

5. What should I know while using ETOPOPHOS?

Things you should do
  • Be sure to keep all your doctor's appointments so your progress can be checked.
  • It is important to have your follow-up infusions of ETOPOPHOS at the appropriate time to get the best effect from your treatments.
  • Remind any doctor, dentist, nurse or pharmacist you visit that you are using ETOPOPHOS.
Driving or using machines
  • ETOPOPHOS may cause dizziness, light-headedness, tiredness, changes of vision, or vomiting in some people. If this occurs do not drive.
  • Be careful driving or operating machinery until you know how ETOPOPHOS affects you.
Drinking alcohol
  • Do not drink alcohol while taking ETOPOPHOS.
Looking after your medicine
  • Store ETOPOPHOS in the refrigerator (2-8°C) and protect from light.

For more information, see Section 5. What should I know while using ETOPOPHOS? in the full CMI.

6. Are there any side effects?

If you get any of the following side effects, tell your doctor immediately or go to Accident and Emergency at your nearest hospital: chills, fever, fast heart beat, wheezing or coughing, difficulty breathing, dizziness, flushing, sweating, and swelling of the face, tongue or other parts of the body.

Tell your doctor or nurse as soon as possible if you notice any of the following: Nausea, vomiting, diarrhoea, stomach pain or discomfort, constipation, altered taste. Unusual hair loss or thinning. Dizziness, light headedness, feeling tired or weak, problems swallowing, low/high blood pressure, hallucinations, muscle cramps or spasms. Infertility. Frequent infections, fever, chills, sore throat, 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. 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. Numbness, tingling and pain in hands or feet, sore mouth, eye pain, vision problems, tiredness, headaches, being short of breath when exercising, dizziness and looking pale, heart problems (e.g. fast heartbeat, heart attack), mouth ulcers, cold sores. Abdominal pain, loss of appetite with yellowing of the skin and eyes. Burning, stinging, pain, redness or swelling at the injection site. Passing little or no urine, drowsiness, nausea, vomiting, breathlessness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

ETOPOPHOS®

Active ingredient: etoposide phosphate (e-TOE-poe-side fos-FATE)


Consumer Medicine Information (CMI)

This leaflet answers some common questions about ETOPOPHOS. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using ETOPOPHOS.

Where to find information in this leaflet:

1. Why am I using ETOPOPHOS?
2. What should I know before I use ETOPOPHOS?
3. What if I am taking other medicines?
4. How do I use ETOPOPHOS?
5. What should I know while using ETOPOPHOS?
6. Are there any side effects?
7. Product details

1. Why am I using ETOPOPHOS?

ETOPOPHOS contains the active ingredient etoposide phosphate an anti-cancer medicine. ETOPOPHOS interferes with the development of cells and causes cell death, particularly in cancer cells.

ETOPOPHOS is used to treat lung cancer, leukaemia (blood cancer), cancer of the lymph glands and testicular cancer.

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

2. What should I know before I use ETOPOPHOS?

Warnings

Do not use ETOPOPHOS if:

  • you are allergic to etoposide phosphate, or any of the ingredients listed at the end of this leaflet.
  • always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

have or have had any medical conditions, especially the following:

  • liver or kidney problems
  • any condition which reduces your blood cell “counts” such as white cells (leukopenia), neutrophils (neutropenia) or platelets (thrombocytopenia).
  • take any medicines for any other condition
  • have an infection or high temperature. 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.
  • have had recent surgery
  • are receiving radiation therapy, which lowers your immune system.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Tell your doctor and do not take ETOPOPHOS if you are pregnant or intend to become pregnant.

Like most medicines used to treat cancer, ETOPOPHOS is not recommended for use during pregnancy, unless you and your doctor have discussed the risks and benefits involved.

You should use some kind of birth control while you are having ETOPOPHOS treatment and for at least 6 months after you stop using ETOPOPHOS.

ETOPOPHOS may cause birth defects if either the male or female is using ETOPOPHOS at the time of conception.

Tell your doctor and do not take ETOPOPHOS if you are breast-feeding or plan to breastfeed, unless you have discussed it with your doctor.

It is not known whether ETOPOPHOS passes into breast milk. Therefore there is a possibility that the breast-fed baby may be affected.

If you have not told your doctor about any of the above, tell them before you start taking ETOPOPHOS.

If you are not sure whether you should take ETOPOPHOS talk to your doctor.

3. What if I am taking other medicines?

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

Some medicines and ETOPOPHOS may interfere with each other. These include:

  • some other medicines or treatments that are used to treat other forms of cancer such as Levamisol (Ergamisol), doxorubicin, epirubicin, daunoribicin, cisplatin, vincristine, radiation therapy and corticosteroids such as prednisone, prednisolone and dexamethasone.
  • ciclosporin a medicine used to prevent rejection of transplanted organs
  • medicines used to treat epilepsy
  • warfarin, a medicine used to reduce blood clotting
  • live viral vaccines
  • some medicines for pain including phenylbutazone and aspirin

These medicines may be affected by ETOPOPHOS, 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.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect ETOPOPHOS.

4. How do I use ETOPOPHOS?

How much is given

Your doctor will decide what dose you will receive. Your dose of ETOPOPHOS injection is worked out based on your body weight and height, the type of cancer you have and other medicines you are taking. The dose worked out for you may be different to the dose for another patient.

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

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 ETOPOPHOS you receive.

How ETOPOPHOS is given

ETOPOPHOS must only be prepared and administered by a doctor or nurse.

ETOPOPHOS injection is given as an infusion (drip) into your veins, over 5 minutes to 3.5 hours.

How long it is given

ETOPOPHOS is usually given each day for 1 to 5 days for lower dose and every other day: days 1,3,5 for higher dose. This is followed by a treatment-free interval of 3-4 weeks. This is called one cycle of chemotherapy. Your doctor will decide how many of these cycles you will need. ETOPOPHOS may be given at the same time as other anti-cancer agents on days 1, 3 and 5 every 3 to 4 weeks.

If you use too much ETOPOPHOS

As your dose of ETOPOPHOS will be determined and administered by a medical specialist the chance of receiving an overdose is most unlikely.

Symptoms of overdose may include collapse, sores and pain in the mouth and throat, fever, chills, weakness, fatigue, headache, confusion, fast heart beat, nausea and vomiting, yellowing of the skin and eyeballs, and lower back or side pain.

If you think you have received more of this medicine than you should, tell your specialist as soon as possible and your specialist will give you the appropriate treatment.

5. What should I know while using ETOPOPHOS?

Things you should do

Be sure to keep all your doctor's appointments and follow up appointments so your progress can be checked.

It is important to have your follow-up infusions of ETOPOPHOS at the appropriate time to get the best effect from your treatments.

Tell your doctor, dentist or pharmacist straight away that you are taking ETOPOPHOS if you:

  • are about to be started on any new medicine
  • plan to have surgery that needs a general anaesthetic

ETOPOPHOS 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 precautions 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 toothbrush, toothpick or dental floss. Your doctor, dentist, nurse or pharmacist may recommend other ways to clean your teeth and gums. Check with your doctor before having any dental work.
  • 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 ETOPOPHOS.

You may feel flushed or get headaches.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ETOPOPHOS affects you.

As with other medicines used to treat cancer, ETOPOPHOS may cause dizziness, light-headedness,tiredness, changes of vision, or vomiting in some people. Make sure you know how you react to ETOPOPHOS 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.

Drinking alcohol

If you drink alcohol, any dizziness or lightheadedness caused by ETOPOHOS may be worse.

Looking after your medicine

ETOPOPHOS will be stored at the Clinic where you are being treated.

ETOPOPHOS vials should be stored in the refrigerator (2-8°C) and protected from light.

Follow the instructions in the carton on how to take care of your medicine properly.

Getting rid of any unwanted medicine

Do not use this medicine after the expiry date.

6. Are there any side effects?

Tell your doctor or nurse as soon as possible if you do not feel well while you are having ETOPOPHOS.

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

See the information below and, if you need to, ask your doctor if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
Gut and digestion-related:
  • nausea
  • vomiting
  • diarrhoea
  • stomach pain or discomfort
  • constipation
  • altered taste
Skin and hair:
  • unusual hair loss or thinning
Other:
  • dizziness, light headedness
  • feeling tired or weak
  • problems swallowing
  • low/high blood pressure
  • hallucinations
  • muscle cramps or spasms
Reproduction:
  • infertility
Tell your doctor or nurse if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of infections such as:
  • frequent infections
  • fever
  • chills
  • sore throat
  • mouth ulcers
Signs of unusual bleeding such as:
  • bleeding or bruising more easily than normal
  • nose bleeds
  • rash of small reddish-purple spots on your skin
  • blood in your stool or urine
Signs of an allergic reaction such as:
  • 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
Other:
  • numbness, tingling and pain in hands or feet
  • sore mouth, eye pain, vision problems
  • tiredness, headaches, being short of breath when exercising, dizziness and looking pale
  • heart problems (e.g. fast heartbeat, heart attack)
  • mouth ulcers
  • cold sores
Signs of liver problems (jaundice or hepatitis) such as:
  • abdominal pain
  • loss of appetite with yellowing of the skin and eyes
Skin and hair:
  • burning, stinging, pain, redness or swelling at the injection site
Signs of kidney problems (when high doses are given which is usually reversible) such as:
  • passing little or no urine
  • drowsiness
  • nausea
  • vomiting
  • breathlessness
Tell your doctor or nurse straight away if you notice any of these serious side effects.
Signs of a sudden life-threatening allergic reaction:
  • chills
  • fever
  • fast heartbeat
  • wheezing or coughing
  • difficulty breathing
  • dizziness
  • flushing
  • sweating
  • swelling of the face, tongue or other parts of the body.
Tell your doctor immediately or go straight to the Emergency Department at your nearest hospital if you notice any of these life-threatening side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

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

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What ETOPOPHOS contains

Active ingredient
(main ingredient)
etoposide phosphate
Other ingredients
(inactive ingredients)
sodium citrate dihydrate
dextran 40
Potential allergensnone

Do not take this medicine if you are allergic to any of these ingredients.

What ETOPOPHOS looks like

ETOPOPHOS is a white to off-white powder in a glass vial, in either 100mg, 500mg, or 1g strengths:

ETOPOPHOS Injection (equivalent to 100mg etoposide) - AUST R 57483

ETOPOPHOS Injection (equivalent to 500mg etoposide) - AUST R 77219

ETOPOPHOS Injection (equivalent to 1g etoposide) - AUST R 77220

Who distributes ETOPOPHOS

Link Medical Products Pty Ltd.
5 Apollo Street,
Warriewood, NSW, 2102
Ph: 1800 181 060
linkhealthcare.com.au

This leaflet was prepared in July 2022.

Published by MIMS April 2023

BRAND INFORMATION

Brand name

Etopophos

Active ingredient

Etoposide

Schedule

S4

 

1 Name of Medicine

Etoposide phosphate.

2 Qualitative and Quantitative Composition

Etopophos injection is available in single use vials. Each vial contains 113.6 mg of etoposide phosphate (equivalent to 100 mg etoposide) as a lyophilised powder for injection.
Etopophos injection is also available in pharmacy bulk vials containing either 568 mg of etoposide phosphate (equivalent to 500 mg etoposide) or 1136 mg of etoposide phosphate (equivalent to 1 g etoposide).
Etoposide phosphate is a water-soluble prodrug of etoposide (VP-16-213), a semi-synthetic derivative of podophyllotoxin, is an anti-neoplastic drug for intravenous use, which can be used alone or in combination with other oncolytic drugs.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Etopophos contains a lyophilised powder form of etoposide phosphate (as the diethanolate).

4 Clinical Particulars

4.1 Therapeutic Indications

Etopophos (etoposide phosphate) 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.
5. Testicular tumours.

4.2 Dose and Method of Administration

Etopophos is administered by slow intravenous infusion. Etopophos should not be given by rapid intravenous injection. The usual dose for etoposide is 50 to 100 mg/m2/day, days 1 to 5 or 100-150 mg/m2/day, days 1, 3 and 5 every 3 to 4 weeks in combination with other agents approved for use in the disease to be treated. Dosage should be modified to take into account the myelosuppressive effects of other medications in the combination or the effects of prior X-ray therapy or chemotherapy which may have compromised bone marrow reserve.
Etopophos may be infused over 5-210 minutes. Contains no antimicrobial agent. The reconstituted solution is for single use only. Discard any residue.

Impaired liver function.

There are indications that 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 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.

Impaired renal function.

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 reductions should be considered in these patients.
Prior to use, the contents of each vial must be reconstituted with sterile water for injection, 5% glucose injection, 0.9% sodium chloride injection, bacteriostatic water for injection with benzyl alcohol, or bacteriostatic sodium chloride for injection with benzyl alcohol to a concentration equivalent to 20 mg/mL or 10 mg/mL etoposide (22.7 mg/mL or 11.4 mg/mL etoposide phosphate), respectively.
Use the following quantity of diluent (see Table 2).
When reconstituted as shown in Table 1, the solution contains 3.3 mg/mL of sodium citrate and 30 mg/mL of dextran 40.
Following reconstitution the solution may be administered without further dilution or it can be further diluted to concentrations as low as 0.1 mg/mL etoposide (0.11 mg/mL etoposide phosphate) with either 5% dextrose injection or 0.9% sodium chloride injection.
When reconstituted as directed, Etopophos solutions are chemically and physically stable when stored in glass or plastic containers under refrigeration 2°-8°C for 7 days; at controlled room temperature 20°-25°C for 24 hours following reconstitution with Sterile Water for Injection, USP, 5% Glucose Injection, USP; or 0.9% Sodium Chloride Injection, USP; or at controlled room temperature 20°-25°C for 48 hours following reconstitution with bacteriostatic water for injection with benzyl alcohol or bacteriostatic sodium chloride for injection with benzyl alcohol.
Solutions of Etopophos should be prepared in an aseptic manner. To reduce microbiological hazard, the reconstituted product and any further dilutions made from it should be used as soon as practicable after reconstitution/ preparation. If storage is necessary hold at 2°-8°C for not more than 24 hours.
Parenteral drug products should be inspected visually for particulate matter and discolouration prior to administration whenever solution and container permit.
The intravenous solution is suitable for infusion in glass or PVC containers.
The pharmacy bulk vials contain a 2% overage and the single use vials a 6% overage to ensure the nominal amount can be withdrawn after reconstitution.

4.3 Contraindications

Etopophos is contraindicated in patients with severe hepatic or renal dysfunction or in those patients who have demonstrated a previous hypersensitivity to etoposide, etoposide phosphate or any component of the formulation.
Etopophos is contraindicated in severe bone marrow failure (WBC less than 2000 cells/mm3 or platelet count less than 75,000 cells/mm3) not due to malignant disease.
Etopophos must not be given by intra-cavity injection.

4.4 Special Warnings and Precautions for Use

Etopophos (etoposide phosphate) 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.
Since etoposide phosphate is rapidly and completely converted to etoposide, the warnings and precautions that are considered when prescribing etoposide should be considered when prescribing Etopophos (etoposide phosphate).

General.

In all instances where the use of Etopophos is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risk of adverse reactions. Most such adverse reactions are reversible if detected early. If severe reactions occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician. Reinstitution of Etopophos therapy should be carried out with caution, and with adequate consideration of the further need for the drug and alertness as to 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 Etopophos 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 Etopophos therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent course of Etopophos: platelet count, haemoglobin, white blood cell count and differential. The occurrence of a platelet count below 50,000/mm3 or an absolute neutrophil count below 500/mm3 is an indication to withhold further therapy until the blood counts have sufficiently recovered.
Dosage should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior X-ray therapy or chemotherapy which may have compromised bone marrow reserves.
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 with caution.

Secondary leukaemia.

The occurrence of acute leukaemia, which can occur with or without a myelodysplastic syndrome, has been described in patients that were treated with VEPESID in association with other antineoplastic drugs.
Neither the cumulative risk, nor the predisposing factors related to the development of secondary leukaemia are known. The roles of both administration schedules and cumulative doses of etoposide have been suggested but have not been clearly defined.
An 11q23 chromosome abnormality has been observed in some cases of secondary leukaemia in patients who have received epipodophyllotoxins. This abnormality has also been seen in patients developing secondary leukaemia after being treated with chemotherapy regimens not containing epipodophyllotoxins and in leukaemia occurring de novo. Another characteristic that has been associated with secondary leukaemia in patients who have received epipodophyllotoxins appears to be a short latency period, with average median time to development of leukaemia being approximately 32 months.

Anaphylactic reactions.

Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension, which can be fatal. Treatment is symptomatic. The administration should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines, or volume expanders at the discretion of the physician.
Cardiac arrest has been reported secondary to acute allergic reactions during the infusion of etoposide, the active form of Etopophos.
Injection site reactions may occur during the administration of Etopophos (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.

Tumour lysis syndrome.

Tumour lysis syndrome (sometimes fatal) has been reported following the use of etoposide in association with other chemotherapeutic drugs. Close monitoring of patients is needed to detect early signs of tumour lysis syndrome, especially in patients with risk factors such as bulky treatment-sensitive tumours, and renal insufficiency. Appropriate preventive measures should also be considered in patients at risk of this complication of therapy.

Use in renal impairment and use in hepatic impairment.

Etopophos should be given cautiously in individuals with a degree of hepatic and renal dysfunction (see Section 4.2 Dose and Method of Administration).
Reversible cases of acute renal failure have been reported with administration of high dose (2220 mg/m2) Etopophos with total body irradiation used for hematopoietic stem cell transplantation. The Etopophos formulation contains dextran 40, which has been associated with acute renal failure when administered in high doses. 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)).

Vaccinations.

Concomitant use of Etopophos 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 defence mechanisms may be suppressed by Etopophos. Vaccination with a live vaccine in a patient taking Etopophos 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).

Mutagenic potential.

Given the mutagenic potential of etoposide, an effective contraception is required for both male and female patients during treatment and up to 6 months after ending treatment. Genetic consultation is recommended if the patient wishes to have children after ending the treatment. As etoposide may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.

Use in the elderly.

No data available.

Paediatric use.

Safety and effectiveness in children have not been systematically studied.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Etopophos should not be physically mixed with any other drug.
Prior or concurrent use of other drugs with similar myelosuppressive action as etoposide may be expected to have additive or synergetic effects.
Caution should be exercised when administering Etopophos with drugs that are known to inhibit phosphatase activities (e.g. levamisole hydrochloride). High dose ciclosporin (concentrations > 2000 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 Etopophos clearance and reduced efficacy, and other antiepileptic therapy may be associated with increased Etopophos clearance and reduced efficacy.
Co-administration of antiepileptic drugs and Etopophos 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.
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).
In vitro plasma protein binding is 97%. Phenylbutazone, sodium salicylate, and acetylsalicylic acid may displace etoposide from plasma protein binding (see Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies with male animals indicate that Etopophos treatment causes irreversible atrophy of the testes with accompanying spermatogenesis defects in the testes and epididymis, and reduced seminal vesicle and prostate secretions.
(Category D)
Etopophos 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 Etopophos is also teratogenic. There are no adequate and well controlled studies in pregnant women. If this medicine is used during pregnancy, or if the patient becomes pregnant while receiving this medicine, the patient should be apprised of the potential hazard to the foetus. Women of childbearing potential should be advised to avoid becoming pregnant.
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.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Etopophos, 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 Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration. Etoposide phosphate may cause adverse reactions that affect the ability to drive and use machines such as fatigue, somnolence, nausea, vomiting, cortical blindness, hypersensitivity reactions with hypotension. Patients who experience such adverse reactions should be advised to avoid driving or using machines.

4.8 Adverse Effects (Undesirable Effects)

Etopophos has been found to be well tolerated as a single agent in clinical studies involving 206 patients with a wide variety of malignancies, and in combination with cisplatin in 60 patients with small cell lung cancer. The most frequent clinically significant adverse experiences were leukopenia and neutropenia.
Unless otherwise stated, the following safety data relate to 98 patients administered single agent Etopophos therapy at or above the recommended dose. Adverse events reported were those occurring during or following the first course of therapy, and have, where possible, been grouped by frequency according to the following criteria. Very common: > 1/10; common: > 1/100 and < 1/10; uncommon: > 1/1,000 and < 1/100; rare: > 1/10,000 and < 1/1,000; very rare: < 1/10,000. See Table 3.
Infection and haemorrhage have been reported.
Reversible acute renal failure has been reported in postmarketing experience (see Section 4.4 Special Warnings and Precautions for Use).
Etopophos was reported to lead to infertility.
Since etoposide phosphate is converted to etoposide, the adverse experiences reported below that are associated with etoposide can be expected to occur with Etopophos.
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. See Table 4.

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

No proven antidotes have been established for Etopophos overdosage.
Metabolic acidosis and cases of serious hepatic toxicity have been reported in patients receiving higher than recommended intravenous doses of etoposide.
Total etoposide doses of 2.4 g/m2 to 3.5 g/m2 administered intravenously over three days have resulted in severe mucositis and myelotoxicity.
For information on the management of an overdose, contact the Poison Information Centre on 131126 (within Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Etoposide phosphate is converted in vivo to the active moiety, etoposide, by dephosphorylation. The mechanism of action of etoposide phosphate is believed to be the same as that of etoposide. Etoposide has been shown to cause metaphase arrest in chick fibroblasts. Its main effect, however, appears to be at the G2 portion of the cell cycle in mammalian cells. 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 does not interfere with microtubular assembly. The predominant macromolecular effect of etoposide appears to be DNA synthesis inhibition.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

A direct comparison of the pharmacokinetic parameters (AUC and Cmax) of etoposide following intravenous administration of molar equivalent doses of Etopophos and etoposide was made in two randomized cross-over studies in patients with a variety of malignancies. Results from both studies demonstrated no statistically significant differences in the AUC and Cmax for etoposide when administered as Etopophos or etoposide. In addition, there were no statistically significant differences in the pharmacodynamic parameters (haematologic toxicity) after administration of Etopophos or etoposide.

Distribution.

On intravenous administration, the disposition of etoposide is best described as a biphasic process with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 11 hours.
The mean volumes of distribution at steady state fall in the range of 18 to 29 litres or 7 to 17/m2. Etoposide enters the CSF poorly. Although it is detectable in CSF and intracerebral tumours, the concentrations are lower than in extracerebral tumours and in plasma. Etoposide concentrations are higher in normal lung than in lung metastases and are similar in primary tumours and normal tissues of the myometrium. In vitro, etoposide is highly protein bound (97%) to human plasma proteins. An inverse relationship between plasma albumin levels and etoposide renal clearance (i.e. higher serum albumin and lower renal clearance) is found in children and adolescents. Phenylbutazone, sodium salicylate and aspirin at concentrations achieved in vivo displace protein-bound etoposide.
Etoposide does not accumulate in the plasma following daily administration of 100 mg/m2 for 4 to 6 days.

Metabolism.

Following intravenous administration of Etopophos, etoposide phosphate is rapidly and completely converted to etoposide in plasma.
The hydroxy acid metabolite [4'-demethylepipodophyllic acid-9-(4,6-0-(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.

Excretion.

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.
Total body clearance values range from 33 to 48 mL/min or 16 to 36 mL/min/m2 and, like the terminal elimination half-life, are independent of dose over a range 100-600 mg/m2. Over the same dose range, the areas under the plasma concentration vs. time curves (AUC) and the maximum plasma concentration (Cmax) values increase linearly with dose.
In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m2 or about 35% of the total body clearance over a dose range of 80 to 600 mg/m2. Etoposide, therefore, is cleared by both renal and non-renal processes, i.e. metabolism and biliary excretion. The effect of renal disease on plasma etoposide clearance is not known.
Biliary excretion of unchanged drug and/or metabolites is an important route of etoposide elimination as faecal recovery of radioactivity is 44% of the intravenous dose. 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 radiolabelled metabolites of 14C-etoposide. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.
Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and higher steady-state volume of distribution (see Section 4.2 Dose and Method of Administration). In children, elevated serum SGPT levels are associated with reduced drug total body clearance. Prior use of cisplatin may also result in a decrease of etoposide total body clearance in children.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

The carcinogenic potential of Etopophos has not been studied. However, based upon its pharmacodynamic mechanism of action, Etopophos is a potential carcinogenic and genotoxic agent. Etoposide has been shown to be mutagenic in mammalian and bacterial cells and Etopophos is expected to have similar mutagenic effects.
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

Dextran 40, Sodium citrate dihydrate.

6.2 Incompatibilities

Etopophos should not be physically mixed with any other drug.
See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

Store at 2°C to 8°C. Protect from light, do not freeze.

6.5 Nature and Contents of Container

Single use vials containing 113.6 mg or pharmacy bulk vials containing 568 mg or 1136 mg etoposide phosphate lyophilised powder. Supplied in pack of 1.

6.6 Special Precautions for Disposal

As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of Etopophos. Skin reactions associated with accidental exposure to etoposide may occur. The use of gloves is recommended. If Etopophos solution contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.
Procedures for proper handling and disposal of anti-cancer agents should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


[5S,5aR,8aR,9S)-5-[3,5-dimethoxy-4-(phosphono oxy) phenyl]-9-[4,6-O-(R)-ethylidene-β-D-glucopyranosyl oxy]-5,8,8a,9-tetrahydroisobenzofuro [5,6-f][1,3]benzodioxol-6(5aH)-one, (as the diethanolate).
Molecular weight: 760.69.
Molecular formula: C29H33O16P.2C2H6O.

CAS number.

The CAS number for etoposide phosphate is 117091-64-2 [USAN] and for etoposide phosphate diethanolate is 149028-00-2 [USAN].

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes