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.

What is in this leaflet

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.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking VEPESID 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 VEPESID is used for

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

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

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

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

Before you are given VEPESID

When you must not be given it

Do not take VEPESID if you have an allergy to VEPESID, or any of the ingredients listed at the end of this leaflet, unless you have discussed it with your doctor.

Symptoms of an allergic reaction may include:

  • chills/fever
  • fast heart beat
  • difficulty in breathing, shortness of breath
  • dizziness or lightheadedness

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

  • liver problems
  • kidney problems
  • your immune system is not working properly (you get a lot of infections requiring treatment with antibiotics)
  • 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
  • lowered immunity due to treatment with medicines such as corticosteroids, cyclosporin or other medicines used to treat cancer

Tell your doctor if you have an infection or high temperature. Your doctor may decide to delay your treatment until the infection has gone.

Do not take VEPESID if you have had recent surgery.

Do not take VEPESID if you are receiving radiation therapy or any other medicine, which lowers your immune system.

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 12 weeks after you stop using it. VEPESID may cause birth defects if either the male or female is using it at the time of conception.

Do not breastfeed while having VEPESID, 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 VEPESID.

If you are not sure whether you should have VEPESID, talk to your doctor.

Before you are given it

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 or have had any medical conditions, especially the following:

  • liver problems
  • kidney problems
  • 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
  • lowered immunity due to treatment with medicines such as corticosteroids, cyclosporin or other medicines used to treat cancer
  • lowered immunity due to treatment with medicines such as corticosteroids, cyclosporin or other medicines used to treat cancer (including radiation therapy)

Tell your doctor if you are pregnant or intend to become pregnant.

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

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

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 VEPESID may interfere with each other. These include:

  • Some other medicines that are used to treat other forms of cancer
  • Cyclosporin - a medicine used to prevent rejection of transplanted organs

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.

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

How VEPESID is given

How much is given

Your doctor will decide what dose you will receive. Your dose of VEPESID capsules are 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 for another patient.

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

Several courses of VEPESID 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 VEPESID you receive.

How it is given

VEPESID capsules may be given to you at the hospital or surgery or you may take them yourself at home. You must only take VEPESID capsules with water preferably on an empty stomach.

If you forget to take VEPESID capsules

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 that you missed. This may increase the chance of you getting an unwanted side effect.

How long it is given

VEPESID 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. VEPESID may be given at the same time as other anti-cancer agents, or may be given alone.

Overdose

Immediately telephone your doctor or pharmacist or the Poisons Information Centre (telephone 13 11 26) or go to Accident or Emergency at your nearest hospital, if you think that you or someone else may have taken too many VEPESID capsules. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

Symptoms of overdose may include collapse, kidney failure, liver failure, failure of the immune system, and continuing nausea and/or vomiting.

While you are using VEPESID

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 VEPESID 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 taking VEPESID.

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

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

If you become pregnant while taking VEPESID, tell your doctor.

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 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 give VEPESID to anyone else, even if they have the same condition as you.

Do not take VEPESID to treat any other complaints unless your doctor tells you to.

Do not stop taking VEPESID, or lower the dose, without checking with your doctor.

Things to be careful of

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

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 VEPESID.

  • nausea, vomiting, diarrhoea, constipation, stomach pain or discomfort
  • loss of appetite, aftertaste
  • sore mouth, problems swallowing
  • unusual hair loss or thinning
  • dizziness
  • feeling tired or down,
  • rash, itchy skin, discolouration of skin

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.

  • 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
  • sore mouth, eye pain, vision problems
  • 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
  • numbness, tingling and pain in hands or feet
  • pain in lungs, shortness of breath or change in breathing, cough, unusual tiredness
  • heart problems (e.g. fast heartbeat)
  • seizures
  • nausea, vomiting, diarrhoea, abdominal pain, loss of appetite with yellowing of the skin and eyes, bleeding, fatigue, weakness, confusion
  • passing little or no urine

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 heart beat, 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 VEPESID

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 previous section.

Storage

VEPESDID capsules should be stored below 25°C.

Do not store VEPESID capsules or any other medicine in the bathroom or near a sink.

Do not leave them in the car on a hot day or on window sills. Heat or dampness can destroy some medicines.

Keep VEPESID capsules where children cannot reach them. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Product description

What it 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. VEPESID 100mg capsules are supplied in blister packs of 10 capsules.

Ingredients

CAPSULES:

Active: The active ingredient in VEPESID capsules is etoposide.
Each capsule either contains 50mg of etoposide or 100mg of etoposide.

Inactive: Each capsule also contains citric acid, glycerol, macrogol 400 gelatin, parabens, titanium dioxide & iron oxide pigment.

Contains hydroxybenzoates.

Sponsored by

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

Australian Registration Numbers:

VEPESID Capsules 100mg - AUST R 10234

VEPESID Capsules 50mg - AUST R 10233

Date of Preparation: December 2019

Further Information

Your doctor is the best person to answer any further questions you may have about VEPESID. 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 VEPESID at any time with your doctor.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

Vepesid

Active ingredient

Etoposide

Schedule

S4

 

1 Name of Medicine

Etoposide.

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.
Molecular weight: 588.58.
Molecular formula: C29H32O13.

Chemical structure.


CAS number.

33419-42-0.

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.

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/square metre 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. (Also see Section 4.8 Adverse Effects (Undesirable Effects), Haematological).

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.

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.

4.3 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.

Anaphylactic reactions.

Physicians should be aware of the possible occurrence of an anaphylactic reaction manifested by chills, fever, tachycardia, bronchospasm, dyspnoea and hypotension. 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).

Use in hepatic and renal impairment.

Vepesid should be given cautiously in individuals with a degree of hepatic and renal dysfunction (see Section 4.2 Dose and Method of Administration, Impaired liver function, Impaired renal function).

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 some minor differences in pharmacokinetic parameters between elderly and nonelderly patients have been observed, these differences were not considered clinically significant. Etoposide and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this 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, Use in hepatic and 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. Vepesid may need to be used with caution in combination chemotherapy.
High dose cyclosporin, 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).

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. As Vepesid may decrease male fertility, preservation of sperm may be considered for the purpose of later fatherhood.
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.

4.8 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 percent and 7 to 17 percent, 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 percent and 4 to 20 percent 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.
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 percent 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, 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 percent 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), 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.

Reporting of 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

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. However see Section 4.2 Dose and Method of Administration, Impaired liver function, Impaired renal function.

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 4.4 Special Warnings and Precautions for Use).
Capsules should be taken with water, preferably on an empty stomach.

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

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).

7 Medicine Schedule (Poisons Standard)

S4.

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.

Summary Table of Changes