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.

What is in this leaflet

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.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking ETOPOPHOS against the benefits they expect it will have for you.

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

Keep this leaflet. You may need to read it again.

What ETOPOPHOS is used for

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

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

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

Your doctor may have prescribed ETOPOPHOS for another reason. Ask your doctor if you have any questions about why ETOPOPHOS was prescribed for you.

Before you are given ETOPOPHOS

When you must not be given it

Do not have ETOPOPHOS if you have an allergy to ETOPOPHOS, or any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include:

  • chills/fever
  • fast heart beat
  • difficulty in breathing, shortness of breath
  • dizziness or light headedness
  • flushing, sweating
  • swelling of the face, tongue or other parts of the body

Do not take ETOPOPHOS if you have, or have had any of the following medical conditions, unless you have discussed it with your doctor:

  • liver problems
  • kidney 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

Tell your doctor if you have allergies to:

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

Tell your doctor if you 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.

Do not take ETOPOPHOS if you have had recent surgery.

Do not take ETOPOPHOS if you are receiving radiation therapy or any other medicines which lower your immune system.

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 and for at least 6 months after you stop using it. ETOPOPHOS may cause birth defects if either the male or female is using it at the time of conception.

Do not breastfeed while having ETOPOPHOS, 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.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any 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:

  • Levamisol (Ergamisol) a medicine that is used to treat some other forms of cancer
  • Cyclosporin a medicine used to prevent rejection of transplanted organs

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.

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

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

How ETOPOPHOS is given

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 and on the type of cancer you have. The dose worked out for you may be different to the dose of another patient.

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

Several courses of ETOPOPHOS 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 ETOPOPHOS you receive.

How is it 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 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. ETOPOPHOS may be given at the same time as other anti-cancer agents on days 1, 3 and 5 every 3 to 4 weeks.

Overdose

As your dose of ETOPOPHOS will be determined and administered by a medical specialist the chance of receiving an overdose is most unlikely. However, if an overdose should be given, your specialist will give you the appropriate treatment. Symptoms of overdose may include, kidney failure, liver failure, failure of the immune system, and inflammation and ulceration of the mouth and stomach. .

While you are using ETOPOPHOS

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 ETOPOPHOS 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 having ETOPOPHOS.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are taking ETOPOPHOS.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are taking ETOPOPHOS.

If you become pregnant while having ETOPOPHOS, tell your doctor.

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 you 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.

Things to be careful of

Be careful driving or operating machinery until you know how ETOPOPHOS affects you. As with other medicines used to treat cancer, ETOPOPHOS may cause dizziness, light-headedness or tiredness 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. If you drink alcohol, dizziness or light-headedness may be worse.

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.

Ask your doctor to answer any questions you may have.

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

These are the more common side effects of ETOPOPHOS.

  • nausea, vomiting or diarrhoea
  • loss of appetite, sore mouth
  • stomach pain, constipation, altered taste
  • unusual hair loss or thinning
  • dizziness, light headedness
  • feeling tired or weak
  • problems swallowing
  • low/high blood pressure

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
  • sore mouth, eye pain, vision problems
  • burning, stinging, pain, redness or swelling at the injection site
  • kidney problems when high doses are given which is usually reversible

Tell your doctor immediately, or go to accident and emergency at your nearest hospital if you notice any of the following signs of a sudden life-threatening allergic reaction:

  • chills, fever, fast heartbeat, wheezing or coughing, difficulty breathing, dizziness, flushing, sweating and swelling of the face, tongue or other parts of the body.

Other side effects not listed above may occur in some patients. Tell your doctor or nurse if you notice anything that is making you feel unwell.

After using ETOPOPHOS

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 previous section.

Storage

ETOPOPHOS will be stored at the Clinic where you are being treated. Unopened vials of ETOPOPHOS injection should be stored in the refrigerator (2-8°C) and protected from the light.

Product description

What it looks like

ETOPOPHOS is a white to off-white powder in a glass vial.

Ingredients

Active: The active ingredient in ETOPOPHOS Injection is etoposide phosphate.

Inactive: Each vial also contains sodium citrate dihydrate and Dextran 40.

Sponsored by

Link Medical Products Pty Ltd.
5 Apollo Street,
Warriewood, NSW, 2102.

Australian Registration Numbers:

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

Date of Preparation: December 2019

Further Information

Your doctor is the best person to answer any further questions you may have about ETOPOPHOS. You should follow any instructions given by your doctor.

Please note that knowledge about the safety of all medicines may change over time. You should discuss any problems you experience with ETOPOPHOS at any time with your doctor.

AU_CMI_Etopophos_V6.0_Dec19

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Etopophos

Active ingredient

Etoposide

Schedule

S4

 

1 Name of Medicine

Etoposide phosphate.

6.7 Physicochemical Properties

[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.

Chemical structure.


CAS number.

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

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).

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.

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.

4.3 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).

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.

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.

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).)

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.

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).

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.
Caution should be exercised when administering Etopophos with drugs that are known to inhibit phosphatase activities (e.g. levamisole hydrochloride). High dose cyclosporin (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).

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.

4.8 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.
Reversible acute renal failure has been reported in postmarketing experience (see Section 4.4 Special Warnings and Precautions for Use).
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.

4.2 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.

4.7 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.

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).

7 Medicine Schedule (Poisons Standard)

S4.

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.

Summary Table of Changes