SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Vepesid Soft Capsules 50 mg

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Pale pink, soft gelatin capsules containing 50 mg etoposide.

Excipients: each 50mg capsules contains 0.47 mg of parahydroxybenzoate.

3. PHARMACEUTICAL FORM

Oral capsules

4. CLINICAL PARTICULARS

4.1. Therapeutic indications

Vepesid is an anti-neoplastic drug for intravenous or oral use, which can be used alone or in combination with other oncolytic drugs.

Present data indicate that Vepesid is applicable in the therapy of: small cell lung cancer, resistant non-seminomatous testicular carcinoma.

4.2. Posology and method of administration

The recommended course of Vepesid capsules is 120-240 mg/m² orally daily, for five consecutive days. The dose of Vepesid capsules is based on the recommended i.v. dose with consideration given to the bioavailability of Vepesid capsules appearing to be dependent upon the dose administered. The bioavailability also varies from patient to patient following any oral dose. This should be taken into consideration when prescribing this medication. In view of significant intra-patient variability, dose adjustments may be required in order to achieve the desired therapeutic effect. As Vepesid produces myelosuppression, courses may not be repeated more frequently than at 21 day intervals. In any case, a repeat course of Vepesid should not be given until the

blood picture has been checked for evidence of myelosuppression and found to be satisfactory.

The capsules should be taken on an empty stomach.

Elderly:

No dosage adjustment is necessary.

Paediatric use:

Safety and effectiveness in children have not been established.

4.3. Contraindications

Vepesid is contra-indicated in patients with severe hepatic dysfunction or in those patients who have demonstrated hypersensitivity to the drug.

4.4 Special warnings and precautions for use

Vepesid should be administered by individuals experienced in the use of antineoplastic therapy.When Vepesid is administered intravenously care should be taken to avoid extravasation.If radiotherapy and/or chemotherapy has been given prior to starting Vepesid treatment, an adequate interval should be allowed to enable the bone marrow to recover.

If the leucocyte count falls below 2,000/mm3, treatment should be suspended until the circulating blood elements have returned to acceptable levels (platelets above 100,000/mm3, leucocytes above 4,000/mm3), this is usually within 10 days.Peripheral blood counts and liver function should be monitored. (See Undesirable Effects.)

Bacterial infections should be brought under control before treatment with Vepesid commences.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 anti-neoplastic 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.

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.

4.5. Interaction with other medicinal products and other forms of interaction

Co-administration of oral etoposide with high doses of cyclosporin (resulting in concentrations above 2000 ng/ml) has led to an 80% increase in etoposide exposure (AUC). Total body clearance of etoposide decreased by 38% compared to etoposide alone.

4.6. Pregnancy and lactation

Vepesid is teratogenic in rats and mice at dose levels equivalent to those employed clinically. There are no adequate and well-controlled studies in pregnant women.

Vepesid should not normally be administered to patients who are pregnant or to mothers who are breast feeding. Women of childbearing potential should be advised to avoid becoming pregnant.

The influence of Vepesid on human reproduction has not been determined. In-vitro tests indicate that Vepesid is mutagenic.

4.7. Effects on ability to drive and use machines

None stated.

4.8. Undesirable effects

Haematological:

The dose limiting toxicity of Vepesid is myelosuppression, predominantly leucopenia and thrombocytopenia. Anaemia occurs infrequently.

The leucocyte count nadir occurs approximately 21 days after treatment.

Alopecia:

Alopecia occurs in approximately two-thirds of patients and is reversible on cessation of therapy.

Gastrointestinal:

Nausea and vomiting are the major gastrointestinal toxicities and occur in over one-third of patients. Anti-emetics are useful in controlling these side effects. Abdominal pain, anorexia, diarrhoea, oesophagitis and stomatitis occur infrequently.

Other Toxicities:

Hypotension may occur following an excessively rapid infusion and may be reversed by slowing the infusion rate.

Anaphylactoid reactions have been reported following administration of Vepesid. Higher rates of anaphylactoid reactions have been reported in children who received infusions at concentrations higher than those recommended. The role that concentration of infusion (or rate of infusion) plays in the development of anaphylactoid reactions is uncertain. These reactions have usually responded to cessation of therapy and administration of pressor agents, corticosteroids, antihistamines or volume expanders as appropriate.

Apnoea with spontaneous resumption of breathing following discontinuation of etoposide injection has been reported. Sudden fatal reactions associated with bronchospasm have been reported. Hypertension and/or flushing have also been reported. Blood pressure usually returns to normal within a few hours after cessation of the infusion.

The use of etoposide has been reported infrequently to cause peripheral neuropathy.

Vepesid has been shown to reach high concentrations in the liver and kidney, thus presenting a potential for accumulation in cases of functional impairment.

Somnolence, fatigue, aftertaste, fever, rash, pigmentation, pruritus, urticaria, dysphagia, transient cortical blindness and a single case of radiation recall dermatitis have also been reported following the administration of Vepesid.

Neoplasms benign, malignant and unspecified:

Tumour lysis syndrome (sometimes fatal) has been reported very rarely (see Section 4.4 Special Warnings and Special Precautions for Use).

4.9 Overdose

No proven antidotes have been established for Vepesid overdosage. Treatment should be symptomatic and supportive.

Total doses of 2.4 to 3.5 g/m² administered i.v. over three days have resulted in severe mucositis and myelotoxicity. Metabolic acidosis and cases of severe hepatic toxicity have been reported in patients receiving higher than recommended doses of etoposide.

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Etoposide is a semi-synthetic derivative of podophyllotoxin.

Experimental data indicate that etoposide arrests the cell cycle in the G phase. Etoposide differs from the vinca alkaloids in that it does not cause an accumulation of cells in metaphase, but prevents cells from entering mitosis or destroys cells in the G phase. The incorporation of thymidine into DNA is inhibited in vitro by etoposide. Etoposide does not interfere with microtubule assembly.

5.2. Pharmacokinetic Properties

Etoposide is approximately 94% protein-bound in human serum. Plasma decay kinetics follow a bi-exponential curve and correspond to a two compartmental model. The mean volume of distribution is approximately 32% of body weight. Etoposide demonstrates relatively poor penetration into the cerebrospinal fluid. Urinary excretion is approximately 45% of an administered dose, 29% being excreted unchanged in 72 hours.

5.3. Pre-clinical Safety Data

No further relevant data.

6.1 List of excipients

Other ingredients:

Citric acid, glycerol, polyethylene glycol 400, water. Gelatin capsules containing glycerol, iron oxide, sodium hydroxybenzoic acid ethyl ester, sodium propyl parahydroxybenzoate, titanium dioxide, water.

6.2.    Incompatibilities

None stated.

6.3.    Shelf Life

36 months

6.4.    Special Precautions for Storage

Do not store above 25°C. Do not open any blister in which there is evidence of capsule leakage.

6.5.    Nature and Contents of Container

Vepesid 50 mg capsules are packed in blister packs of 20 capsules, each capsule containing 50 mg etoposide.

6.6 Special precautions for disposal and other handling

Vepesid should be administered by individuals experienced in the use of antineoplastic therapy.

Bristol-Myers Squibb Holdings Limited t/a Bristol-Myers Pharmaceuticals Uxbridge Business Park Sanderson Road,

Uxbridge, Middlesex,

UB81DH

8. MARKETING AUTHORISATION NUMBER(S)

Vepesid Capsules 50 mg PL 0125/0153

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

29 April 1983 / 11 September 1996

10 DATE OF REVISION OF THE TEXT

13/03/2008