Summary of Product Characteristics

1.    Name of the medicinal product

Etopophos 100mg Powder for Solution for Injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains etoposide phosphate equivalent to 100 mg etoposide.

Each vial also contains 7.64 mg (0.33mmol) sodium

For full list of excipients, see section 6.1

3    PHARMACEUTICAL FORM

Powder for Solution for Injection.

White to off-white lyophilised powder.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

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

Posology and method of administration

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

Etopophos is administered by slow intravenous infusion. ETOPOPHOS SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

The recommended course of Etopophos Injection is 60-120 mg/m², (etoposide equivalent) i.v daily for five consecutive days. As Etopophos produces myelosuppression, courses should not be repeated more frequently than at 21 day intervals. In any case, repeat courses of Etopophos should not be given until the blood picture has been checked for evidence of myelosuppression and found to be satisfactory.

When used as part of combination therapy, the dosage should be reduced toward the lower end of the dosage range to take into account the myelosuppressive effects of radiation therapy or chemotherapy which may have compromised bone marrow reserve.

Immediately prior to administration, the content of each vial must be reconstituted with either 5 ml or 10 ml Water for Injections B.P., 5% Glucose Intravenous Infusion B.P. or 0.9% Sodium Chloride Intravenous Infusion B.P. to a concentration equivalent to 20 mg/ml or 10 mg/ml etoposide (22.7 mg/ml or 11.4 mg/ml etoposide phosphate) respectively. Following reconstitution the solution may be administered without further dilution or it can be further diluted to concentrations as low as 0.1 mg/ml etoposide (0.14 mg/ml etoposide phosphate) with either 5% Glucose Intravenous Infusion B.P. or 0.9% Sodium Chloride Intravenous Infusion B.P.

Etopophos solutions may be infused over 5 minutes to 3.5 hours.

Care should be taken to avoid extravasation. Occasionally following extravasation of etoposide, soft tissue irritation and inflammation has occurred, ulceration was generally not seen.

Elderly:

No dosage adjustment is necessary.

Paediatric use:

Safety and effectiveness in children have not been established. Until further data are available, Etopophos should not be given to children under 12 years of age.

4.3. Contra-indications

Etopophos is contra-indicated in patients with severe hepatic dysfunction or in those patients who have demonstrated hypersensitivity to etoposide, etoposide phosphate or any other component of the formulation.

4.4 Special warnings and precautions for use

Since etoposide phosphate is rapidly and completely converted to etoposide, the WARNINGS and PRECAUTIONS that are considered when prescribing etoposide should be considered when prescribing Etopophos.

When Etopophos is administered intravenously care should be taken to avoid extravasation. Injection site reactions may occur during the administration of Etopophos (see Undesirable Effects). Given the possibility of extravasation, it is recommended to closely monitor the infusion site for possible infiltration during drug administration. A specific treatment for extravasation reactions is unknown at this time.

If radiotherapy and/or chemotherapy has been given prior to starting Etopophos 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 Etopophos commences.

No data are available on the use of Etopophos in patients with renal and hepatic impairment.

The occurrence of acute leukaemia, which can occur with or without myelodysplasia has been reported rarely in patients treated with etoposide containing regimens.

4.5 Interaction with other medicinal products and other forms of interaction

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

High dose cyclosporin (resulting in concentrations

>2000 ng/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.

In children, elevated 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.

4.6 Fertility, pregnancy and lactation

Etopophos can cause foetal harm when administered to pregnant women. Etoposide is teratogenic in rats and mice at dose levels equivalent to those employed clinically and it is therefore assumed that Etopophos is also teratogenic in humans. There are no adequate and well-controlled studies in pregnant women.

Women of childbearing potential should be advised to avoid becoming pregnant. If Etopophos is used during pregnancy, or if the patient becomes pregnant while receiving this product, the patient should be appraised of the potential hazard to the foetus.

The influence of etoposide on human reproduction has not been determined (see 5.3, preclinical safety data).

It is not known whether Etopophos is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Etopophos, a decision should be made whether to discontinue nursing or to discontinue Etopophos, taking into account the importance of Etopophos to he mother.

4.7. Effects on Ability to Drive and Use Machines

None.

4.8 Undesirable effects

In clinical studies with Etopophos the most frequent clinically significant adverse experiences were leucopenia and neutropenia which occurred in almost all patients. The leucopenia was severe in approximately 20% of the patients, with neutropenia severe in about one third. Thrombocytopenia was reported in about a quarter of the patients and was severe in about 10% of the cases. Anaemia was observed in about three quarters of the patients and was severe in about 20%. Gastrointestinal adverse events were usually mild to moderate. Nausea and/or vomiting was seen in about a third of the patients. Anorexia and mucositis was reported by 10-20% of the patients and constipation, abdominal pain, diarrhoea and taste alteration was seen in between 5 to 10%. Asthenia or malaise affected about a third of the patients. Alopecia was also observed in a third of the patients. Chills and/or fever were reported in a quarter of the patients, dizziness and extravasation/phlebitis in about 5% of the patients. No cardiovascular symptoms including hypotension, have been observed during administration of 5 minute infusions of Etopophos.

Since etoposide phosphate is converted to etoposide, the adverse experiences reported below that are associated with etoposide may occur with Etopophos.

The following data on adverse reactions are based on both oral and intravenous administration of etoposide.

Haematological:

The dose limiting toxicity of etoposide 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 of etoposide and may be reversed by slowing the infusion rate. Symptomatic hypotension has not been seen with Etopophos.

Anaphylactoid reactions have been reported following administration of etoposide. 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.

Etoposide 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 etoposide.

Local soft tissue toxicity has been reported following extravasation of Etopophos.

Infiltration of Etopophos may result in swelling, pain, cellulitis and necrosis including skin necrosis.

4.9. Overdose

Total etoposide doses of 2.4 g/m² to 3.5 administered intravenously 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.

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

5. PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic Properties

Etoposide phosphate is converted in vivo to the active moiety, etoposide, by dephosphorylation. The mechanism of action of etoposide phosphate is believed to be the same as that of etoposide.

Etoposide is a semi-synthetic 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 metaphase, but prevents cells from entering mitosis or destroys cells in the G2 phase. The incorporation of thymidine into DNA is inhibited in vitro by etoposide.

5.2. Pharmacokinetic Properties

Following intravenous administration of Etopophos, etoposide phosphate is rapidly and completely converted to etoposide in plasma. A direct comparison of the pharmacokinetic parameters (AUC and CMAX) of etoposide following intravenous administration of molar equivalent doses of Etopophos and etoposide was made in two randomised cross-over studies in patients. Results from both studies demonstrated no statistically significant differences in the AUC and CMAX for etoposide when administered as Etopophos or etoposide. In addition, there were no statistically significant differences in the pharmacodynamic parameters (haematologic toxicity) after administration of Etopophos or etoposide. Because of the pharmacokinetic and pharmacodynamic bioequivalence of Etopophos to etoposide, the following information on etoposide should be considered.

In vitro, etoposide is highly protein bound (97%) to human plasma proteins. In a study of the effects of other therapeutic agents on in vitro binding of ¹⁴C etoposide to human serum proteins, only sodium salicylate, and aspirin displaced protein-bound etoposide at concentrations generally achieved in vivo. 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.

Etoposide is cleared by both renal metabolism and biliary excretion. Patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC and lower steady state volume of distribution.

Pre-clinical Safety Data

The carcinogenic potential of Etopophos has not been studied. However, based upon its pharmacodynamic mechanism of action, Etopophos is a potential carcinogenic and genotoxic agent. Etoposide has been shown to be mutagenic in mammalian cells and Etopophos is expected to have similar mutagenic effects.

6    PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Dextran 40, sodium citrate dihydrate.

6.2. Incompatibilities

Etopophos should not be physically mixed with any other drug. 6.3    Shelf life

18 months.

Chemical and physical in-use stability has been demonstrated for 7 days at 2-8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 7 days at 2-8 °C, unless dilution has taken place in controlled and validated aseptic conditions.

When reconstituted as directed, Etopophos solutions can be stored in glass or plastic containers under refrigeration (2-8°C) for 7 days; at controlled room temperature 20-25°C for 24 hours following reconstitution with Sterile Water for Injection, USP, 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP; or at controlled room temperature 20-25°C for 48 hours following reconstitution with Bacteriostatic

Water for Injection with Benzyl Alcohol or Bacteriostatic Sodium Chloride for Injection with Benzyl Alcohol. Etopophos solutions further diluted as directed can be stored under refrigeration (2-8°C) or at controlled room temperature 20-25°C for 24 hours.

6.4 Special precautions for storage

Store between 2-8°C. Keep vial in the outer carton.

6.5. Nature and Contents of Container

20ml flint glass type I vial with a butyl rubber stopper and flip-off aluminium seal.

6.6 Special precautions for disposal

Immediately prior to administration, the content of each vial must be reconstituted with either 5 ml or 10 ml Water for Injection B.P. , 5% Glucose Intravenous Infusion B.P. or 0.9% Sodium Chloride Intravenous Infusion BP to a concentration equivalent to 20 mg/ml or 10 mg/ml etoposide (22.7 mg/ml or 11.4 mg/ml etoposide phosphate), respectively. Following reconstitution the solution may be administered without further dilution or it can be further diluted to concentrations as low as 0.1 mg/mL etoposide (0.14 mg/ml etoposide phosphate) with either 5% Glucose Intravenous Infusion BP or 0.9% Sodium Chloride Intravenous Infusion BP.

Etopophos should not be physically mixed with any other drug. Guidelines for the safe handling of anti-neoplastic agents:

1.    Trained personnel should reconstitute the drug.

2.    This should be performed in a designated area.

3.    Adequate protective gloves should be worn.

4.    Precautions should be taken to avoid the drug accidentally coming into contact with the eyes. In the event of contact with the eyes, irrigate with large amounts of water and/or saline.

5.    The cytotoxic preparation should not be handled by pregnant staff.

6.    Adequate care and precautions should be taken in the disposal of items (syringes, needles etc) used to reconstitute cytotoxic drugs. Excess material and body waste may be disposed of by placing in double sealed polythene bags and incinerating at a temperature of 1,000°C. Liquid waste may be flushed with copious amounts of water.

7.    The work surface should be covered with disposable plastic backed absorbent paper.

8.    Use Luer-Lock fittings on all syringes and sets. Large bore needles are recommended to minimise pressure and the possible formation of aerosols. The latter may also be reduced by the use of a venting needle.

7.    MARKETING AUTHORISATION HOLDER

Bristol-Myers Squibb Pharmaceuticals Limited Uxbridge Business Park Sanderson Road,

Uxbridge, Middlesex,

UB81DH

8.    MARKETING AUTHORISATION NUMBER(S)

PL 11184/0052

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/11/2001

10    DATE OF REVISION OF THE TEXT

05/11/2010