Bristol-Myers Squibb Holdings Limited

Vepesid Soft Capsules 50mg

Vepesid Soft Capsules 100mg

Soft gelatin capsules containing 50mg or 100mg etoposide.

Excipients: each capsules contains 0.47 or 0.61 mg of parahydroxybenzoate.

For a full list of excipients, see Section 6.1.

Soft capsule.

Opaque, pink, oval, soft gelatin capsule.

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

Hodgkin's disease

Lymphosarcoma

Acute myeloid leukaemia

Resistant non-seminomatous testicular carcinoma

The usual dose is 120-240 mg/m² which should be given daily, for five consecutive days. The capsules should be taken on an empty stomach. 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, repeat courses of Vepesid should not be given until the blood picture has been checked for evidence of myelosuppression and found to be satisfactory.

Elderly: No dosage adjustment is necessary.

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

Vepesid should only be used under the supervision of a specialist oncology service having the facilities for appropriate monitoring of clinical, biochemical and haematological effects during and after administration.

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 2000/mm³, treatment should be suspended until the circulating blood elements have returned to acceptable levels (platelets above 100,000/mm³, leucocytes above 4000/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 product should be used with care in patients with respiratory dysfunction. Pulmonary function should be monitored regularly.

Vepesid is mutagenic and carcinogenic. The possibility of a carinogenic or mutagenic effect should be borne in mind when designing long term therapy.

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.

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.

None known.

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.

None known.

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.

Cardiovascular: Cardiac arrhythmias, cardiac ischemia and cardiac failure may occur rarely when etoposide is used in combination with other anti-neoplastic therapies. However, it is currently unknown if the cause of the cardiac events is the disease, underlying cardiovascular disorders, prior or concomitant administration of potentially cardiotoxic therapy, or a combination of any of these factors.

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 Precautions for Use).

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.

Etoposide is a semisynthetic derivative of podophyllotoxin.

Experimental data indicate that etoposide arrests the cell cycle in the G₂ phase. Etoposide differs from the vinca alkaloids in that it does not cause an accumulation of cells in the metaphase, but prevents cells from entering mitosis or destroys cells in the G₂ phase. The incorporation of the thymidine into DNA is inhibited in-vitro by etoposide. Etoposide does not interfere with microtubule assembly.

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.

No further relevant data.

Citric acid, anhydrous

Glycerol

Macrogol 400

Purified water

Gelatin capsules containing:

Glycerol

Iron oxide (E172)

Sodium hydroxybenzoic acid ethyl ester

Sodium propyl parahydroxybenzoate (E217)

Titanium dioxide (E171)

Purified water.

Not applicable.

3 years.

Do not store above 25°C.

Vepesid 50 mg capsules are packed in Aclar foil blisters constructed of PVC/Aclar/ aluminium. Each pack contains 20 capsules.

Vepesid 100mg Capsules are packed in Aclar foil blisters constructed of PVC/Aclar/ aluminium. Each pack contains 10 capsules.

Do not open any blister in which there is evidence of capsule leakage.

Bristol-Myers Squibb Holdings Limited

t/a Bristol-Myers Pharmaceuticals

Swords

County Dublin

May 2007

POM