Consumer medicine information

Vepesid

Etoposide

BRAND INFORMATION

Brand name

Vepesid

Active ingredient

Etoposide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Vepesid.

SUMMARY CMI

VEPESID®

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 VEPESID?

VEPESID contains the active ingredient etoposide. VEPESID is used to treat certain types of lung cancer, leukaemia (blood cancer) and lymphoma (cancer of the lymph glands).

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

2. What should I know before I use VEPESID?

Do not use if you have ever had an allergic reaction to etoposide 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 VEPESID? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with VEPESID 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 VEPESID?

  • VEPESID capsules may be given to you at the hospital or out patient clinic, or you may take them yourself at home
  • You should take VEPESID capsules with water preferably on an empty stomach
  • VEPESID is usually given each day for between 3 and 5 days. This is followed by a treatment-free interval of 2-4 weeks.

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

5. What should I know while using VEPESID?

Things you should do
  • Be sure to keep all your doctor's appointments so your progress can be checked
  • Remind any doctor, dentist, nurse or pharmacist you visit that you are using VEPESID
Things you should not do
  • Do not stop using this medicine or change the dosage without checking with your doctor
Driving or using machines
  • VEPESID 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 VEPESID affects you
Looking after your medicine
  • Store VEPESID below 25°C, in a dark place, protected from light, where children cannot reach it

For more information, see Section 5. What should I know while using VEPESID? 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. Loss of appetite, aftertaste, sore mouth, problems swallowing, dizziness, feeling tired or down. Rash, itchy skin, discolouration of skin, unusual hair loss or thinning. Infertility. 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. 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. Nausea, vomiting, diarrhoea, abdominal pain, loss of appetite with yellowing of the skin and eyes, bleeding, fatigue, weakness, confusion, passing little or no urine. 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. Pain in lungs, shortness of breath or change in breathing, cough, unusual tiredness, heart problems (e.g. fast heartbeat, heart attack), seizures, hallucinations, muscle cramps or spasms, mouth ulcers and cold sores.

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

VEPESID®

Active ingredient: etoposide (e-TOE-poe-side)

Consumer Medicine Information (CMI)

This leaflet answers some common questions about VEPESID. 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 VEPESID.

Where to find information in this leaflet:

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

1. Why am I using VEPESID?

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

VEPESID is used to treat certain types of lung cancer, leukaemia (blood cancer) and cancer of the lymph glands.

VEPESID may be used alone or in combination with other medicines to treat cancer. Your doctor will inform you if this is necessary.

2. What should I know before I use VEPESID?

Warnings

Do not use VEPESID if:

  • you are allergic to etoposide, 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
  • infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone.
  • 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 VEPESID if you are pregnant or intend to become pregnant.

Like most medicines used to treat cancer, VEPESID 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 VEPESID and for at least 6 months after you stop using it.

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

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

It is not known whether VEPESID 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 VEPESID.

If you are not sure whether you should have VEPESID, 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 VEPESID may interfere with each other. These include:

  • some other medicines or treatments that are used to treat other forms of cancer such as 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 VEPESID, 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 VEPESID.

4. How do I use VEPESID?

How much to take

Your doctor will decide what dose you will receive. Your dose of VEPESID capsules 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.

VEPESID 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 VEPESID you receive.

How to take VEPESID

VEPESID capsules may be given to you at the hospital or out patient clinic or you may take them yourself at home. You should only take VEPESID capsules with water, preferably on an empty stomach.

How long it is given

VEPESID is usually given each day for between 3 and 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. VEPESID may be given at the same time as other anti-cancer agents, or may be given alone.

If you forget to take VEPESID

If you are taking VEPESID capsules at home and you forget to take a dose - if it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose you missed.

If you use too much VEPESID

If you think that you have used too much VEPESID, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

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

5. What should I know while using VEPESID?

Things you should do

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

Remind any doctor, dentist, nurse or pharmacist you visit that you are using VEPESID.

Because VEPESID destroys blood cells, regular blood tests will be taken during treatment to check your blood cell counts.

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

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

VEPESID 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 if 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

  • give VEPESID to anyone else, even if they have the same condition as you.
  • take VEPESID to treat any other complaints unless your doctor tells you to.
  • stop taking VEPESID, or lower the dose, without checking with your doctor.

Driving or using machines

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

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

Looking after your medicine

  • VEPESDID capsules should be stored below 25°C

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

Store it in a cool dry place away from moisture, heat or sunlight where the temperature stays below 25°C; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

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 VEPESID.

Like other medicines that treat cancer, VEPESID 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
Other:
  • loss of appetite, aftertaste
  • sore mouth, problems swallowing
  • dizziness
  • feeling tired or down
  • mouth ulcers
  • cold sores
Skin and hair:
  • rash, itchy skin, discolouration of skin
  • unusual hair loss or thinning
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 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
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 liver problems (jaundice or hepatitis) such as:
  • nausea
  • vomiting
  • diarrhoea
  • abdominal pain
  • loss of appetite with yellowing of the skin and eyes
  • bleeding
  • fatigue
  • weakness
  • confusion
  • passing little or no urine
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
  • pain in lungs, shortness of breath or change in breathing, cough, unusual tiredness
  • heart problems (e.g. fast heartbeat, heart attack)
  • seizures
  • hallucinations
  • muscle cramps or spasms
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 heart beat
  • 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 nurse 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 VEPESID may take some time to occur. Therefore, even after you have finished your VEPESID 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 VEPESID contains

Active ingredient
(main ingredient)		etoposide
Other ingredients
(inactive ingredients)		citric acid
gelatin
glycerol
macrogol 400
titanium dioxide
iron oxide red
Potential allergenscontains hydroxybenzoates

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

What VEPESID looks like

VEPESID capsules are pink oblong capsules, in either 50mg or 100mg strengths. VEPESID 50mg capsules are supplied in blister packs of either 10 or 20 capsules (AUST R 10233). VEPESID 100mg capsules are supplied in blister packs of 10 capsules (AUST R 10234).

Who distributes VEPESID

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

Vepesid

Active ingredient

Etoposide

Schedule

S4

 

1 Name of Medicine

Etoposide.

2 Qualitative and Quantitative Composition

Vepesid capsules contain 50 or 100 mg etoposide.

Excipients with known effect.

Each 50 mg capsule contains 930 mcg of sodium ethyl hydroxybenzoate and 470 mcg sodium propyl hydroxybenzoate.
Each 100 mg capsule contains 1.22 mg of sodium ethyl hydroxybenzoate and 610 mcg sodium propyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Opaque, pink, soft gelatin capsule.

4 Clinical Particulars

4.1 Therapeutic Indications

Vepesid (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

Vepesid should only be administered and monitored under the supervision of a qualified physician experienced in the use of anti-neoplastic medicinal products.
Biological activity appears to be schedule dependent with multiple dosage over 3-5 days showing superiority over single dose administration.

Adult.

Absorption from the oral route is variable (range 17-74% of intravenous dose in one trial, 25-80% in another, the corresponding means being 50 and 53%).
Dosages should be titrated to achieve maximum therapeutic effect and to minimise toxicity. The suggested starting dose is approximately 100-200 mg/m2/day on days 1 to 5.
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 reserve.
Total dose should not exceed 650 mg/m2 per course.
Capsules should be taken on an empty stomach.

Paediatric.

Specific paediatric dosages have not been evaluated.

Use in the elderly.

As for adults (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Impaired liver function.

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.

Impaired renal function.

In patients with impaired renal function, the following initial dose modification should be considered based on measured creatinine clearance.
Subsequent dosing should be based on patient tolerance and clinical effect. Data are not available in patients with creatinine clearance < 15 mL/min (see Section 4.3 Contraindications).

Instructions to be given to patients.

Patients should be warned that nausea and reversible alopecia may occur as a result of Vepesid therapy.
Patients would be advised to use adequate contraceptive measures during treatment with Vepesid (see Section 4.6 Fertility, Pregnancy and Lactation).
Capsules should be taken with water, preferably on an empty stomach.

4.3 Contraindications

1. Patients with severe hepatic dysfunction.
2. Patients with severely impaired renal function (creatinine clearance < 15 mL/min).
3. Patients who have a demonstrated hypersensitivity to etoposide, etoposide phosphate, or any of the ingredients.
4. Severe bone marrow failure (WBC less than 2000 cells/mm3 or platelet count less than 75,000 cells/mm3) not due to malignant disease.

4.4 Special Warnings and Precautions for Use

Vepesid (etoposide) 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.

General.

In all instances where the use of Vepesid 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 Vepesid 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 Vepesid 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 Vepesid therapy. Therefore, the following studies should be obtained at the start of therapy and prior to each subsequent course of Vepesid: 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 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. Administration of Vepesid should be terminated immediately, followed by the administration of pressor agents, corticosteroids, antihistamines or volume expanders at the discretion of the physician.

Vaccinations.

Concomitant use of Vepesid 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 Vepesid. Vaccination with a live vaccine in a patient taking Vepesid 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).

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.

Other warnings.

Vepesid contains sodium ethyl parahydroxybenzoate and sodium propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

Renal impairment.

In patients with moderate (CrCl = 15 to 50 mL/min), or severe (CrCl < 15 mL/min) renal impairment undergoing haemodialysis, etoposide should be administered at a reduced dose. Haematological parameters should be measured and dose adjustments in subsequent cycles considered based on haematological toxicity and clinical effect in moderate and severe renal impaired patients (see Section 4.2 Dose and Method of Administration, Impaired renal function).

Hepatic impairment.

Patients with impaired hepatic function should regularly have their hepatic function monitored due to the risk of accumulation.

Use in the elderly.

Clinical studies of Vepesid (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 Vepesid 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, comparisons 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 leukopenia 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 age 65 years or more. WHO grade III or IV leukopenia, granulocytopenia, and asthenia were more frequent among elderly patients, post marketing experience also suggests that elderly patients may be more sensitive to some of the known adverse effects of etoposide, including myelosuppression, gastrointestinal effects, infectious complication and alopecia.
Although minor differences in pharmacokinetic parameters between patients ≤ 65 years and > 65 years of age have been observed, these are 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 drug 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 4.4 Special Warnings and Precautions for Use, Hepatic impairment, Renal impairment) for recommended dosing adjustments in patients with renal impairment).

Paediatric use.

Safety and effectiveness in children have not been systematically studied.

Effects on laboratory tests.

Periodic complete blood counts, hepatic and renal function tests and serum urate should be done during the course of Vepesid treatment. They should be performed prior to therapy and at appropriate periods during therapy. At least one determination should be done prior to each course of Vepesid.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Single case reports exist of increased bone marrow depression and possible increased risk of anthracycline-induced cardiomyopathy. Prior or concurrent use of other drugs with similar myelosuppressive action as etoposide may be expected to have additive or synergetic effects. Vepesid may need to be used with caution in combination chemotherapy.
High dose ciclosporin, resulting in concentrations above 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 Vepesid clearance and reduced efficacy, and other antiepileptic therapy may be associated with increased Vepesid clearance and reduced efficacy.
Co-administration of antiepileptic drugs and Vepesid 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.

As Vepesid may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.
(Category D)
Vepesid can cause foetal harm when administered to pregnant women. Vepesid has been shown to be teratogenic in mice and rats. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, 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 Vepesid, 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.
Vepesid 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. Vepesid caused a dose-related maternal toxicity, embryotoxicity and teratogenicity at dose levels of 0.13 mg/kg/day and higher administered intravenously. Embryonic resorptions were 90 and 100 percent at the two highest dosages. At 0.4 and 1.2 mg/kg, foetal weights were 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 Vepesid 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 malformation.
 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 Vepesid, 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 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)

The incidences of adverse reactions, given below as mean percent, are derived from studies that used single agent Vepesid 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 nadirs occurring 7 to 14 days, and platelet nadirs 9 to 16 days, after drug administration. Bone marrow recovery is usually complete by day 20, and no cumulative toxicity has been reported. Leukopenia (less than 4,000 cells/mm3) and severe leukopenia (less than 1,000 cells/mm3) were observed in 60 to 91% and 7 to 17%, respectively, of patients treated with single agent Vepesid. Thrombocytopenia (less than 100,000 platelets/mm3) and severe thrombocytopenia (less than 50,000 platelets/mm3) were seen in 28 to 41% and 4 to 20% of this group of patients. Pancytopenia was found in 7% of 340 patients treated with 50-60 mg/m2 etoposide I.V. for 5 days.
Infection and haemorrhage have been reported.
The occurrence of acute nonlymphocytic leukaemia with or without a preleukaemic phase has been reported in patients treated with Vepesid in association with other antineoplastic agents, in particular, cisplatin.

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 and can usually be controlled by antiemetic therapy. Anorexia, stomatitis and diarrhoea have also been reported.

Cardiovascular.

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. Myocardial infarction and arrhythmia have been reported.

Metabolic complications.

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

Less common reactions.

Allergic.

Anaphylactic-like reactions manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension which can be fatal, have occurred very rarely in patients treated with oral capsules. These reactions have usually responded promptly to the administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate.

Neuropathy.

The use of Vepesid has been reported to cause peripheral neuropathy in 0.7% of patients. The associated use of vincristine sulphate can possibly enhance this neuropathy.
Caution should be taken when given 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: interstitial pneumonitis/ pulmonary fibrosis, seizures (occasionally associated with allergic reactions), central nervous system toxicity (somnolence and fatigue), liver toxicity (transient jaundice and elevated alkaline phosphatase, alanine aminotransferase, and aspartate amino transferase), renal toxicity (elevated urea, hyperuricaemia), septicaemia during high dose regimens, aftertaste, mucositis, stomatitis, esophagitis, fever, Stevens-Johnson syndrome, toxic epidermal necrolysis (one fatal case has been reported), rash, pigmentation, pruritus, urticaria, abdominal pain, constipation, dysphagia, asthenia, malaise, transient cortical blindness, a single report of radiation recall dermatitis and optic neuritis. One case of myocardial infarction has been reported in a patient also treated with mediastinal radiation. There is one case report of a possible drug-related life-threatening cardiotoxicity. Bronchospasm and apnoea have been reported.
Vepesid was reported to lead to infertility.

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

Mucositis, myelotoxicity and metabolic acidosis and in cases of serious hepatic toxicity have been reported in patients receiving higher than recommended doses of etoposide.
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. 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.

Absorption from the oral route of administration is variable and incomplete. Peak blood levels occur about one hour after oral administration.

Bioavailability.

While the absolute bioavailability averaged approximately 55% there were considerable variations between subjects (17-74%) and in one study within individual subjects.

Distribution.

Following intravenous administration of 100 mg etoposide, the peak plasma concentration ranged from 2.2-6.1 micrograms/mL with an average of 4.7, and time to peak ranged from 0.5-2.0 hours (average 1 hour). Only small levels are found in the cerebrospinal fluid, compared with plasma levels.
In a limited number of children, etoposide administered in a dose of 200-250 mg/m2 produced a mean plasma clearance of 17.8 ± 11.2 (SD) mL/min/m2 based on a model-independent method. The elimination half-life based on a model-dependent method averaged 5.8 ± 3.2 hours.
Etoposide is stored extensively in the tissues and has a volume of distribution during terminal phase of excretion of 28 L.

Protein binding.

In vitro, etoposide is highly protein bound (97%) to human plasma 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.

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. In addition, O-demethylation of the dimethoxyphenol ring occurs through the CYP450 3A4 isoenzyme pathway to produce the corresponding catechol.

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.
Renal clearance 13.6 ± 4.5 mL/min; total body clearance 47 ± 22 mL/min. The one metabolite identified has a renal clearance of 31.3 mL/min and total clearance of 111.7 mL/min. In children, approximately 55% of the dose is excreted in the urine as etoposide in 24 hours.
Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and higher steady state volume of distribution. In one study, clearance was reduced by 30% in patients with serum creatinine > 130 micromol/L compared with patients with serum creatinine < 100 micromol/L. In children, elevated serum ALT (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.
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. 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. Glucuronide and/or sulphate 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.

Half-life.

Etoposide shows a biexponential 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 drug can be accounted for by unchanged or metabolised drug excreted in the urine or faeces, indicating prolonged tissue storage. The fact that approximately 30% of the administered dose is excreted unchanged by the kidneys indicates that the dosage may need to be adjusted in patients with renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

Vepesid induced aberrations in chromosome number and structure in embryonic murine cells.

Carcinogenicity.

Six-month chronic toxicity studies in rats have shown Vepesid to have oncogenetic potential but two-year carcinogenicity tests with Vepesid have not been conducted in laboratory animals. Given its mechanism of action, it should be considered a possible carcinogen in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

The inactive ingredients of the capsule content are: citric acid, glycerol, macrogol 400 and purified water.
The soft gelatin capsules contain: gelatin, glycerol, sodium ethyl hydroxybenzoate, sodium propyl hydroxybenzoate, titanium dioxide and iron oxide red.

6.2 Incompatibilities

Incompatibilities were either not assessed or identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Vepesid 50 mg capsules are supplied in blister packs of 10* and 20 capsules.
Vepesid 100 mg capsules are supplied in blister packs of 10 capsules.
* Not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published and should be used appropriately.

6.7 Physicochemical Properties

Vepesid (etoposide; commonly known as VP-16-213 or VP-16) is a semisynthetic derivative of podophyllotoxin used in the treatment of certain neoplastic diseases. It is 4'-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-glucopyranoside]. It is very soluble in methanol and chloroform, slightly soluble in ethanol and sparingly soluble in water and ether. It is made more miscible with water by means of organic solvents.

Chemical structure.


Molecular weight: 588.58.
Molecular formula: C29H32O13.

CAS number.

33419-42-0.

7 Medicine Schedule (Poisons Standard)

Prescription Medicine (S4).

Summary Table of Changes