BEROMUN Powder for solution for infusion Ref.[9704] Active ingredients: Tasonermin

This treatment should be undertaken in specialised centres by surgical teams experienced in the management of limb sarcomas and ILP procedure, with an intensive care unit readily available and with the facilities for continuous monitoring for medicinal product leakage into the systemic circulation.

Posology

Beromun

Upper limb: 3 mg total dose by ILP

Lower limb: 4 mg total dose by ILP

Melphalan

Melphalan dose should be calculated according to the litre-volume method of Wieberdink (Wieberdink J, Benckhuysen C, Braat RP, van Slooten EA, Olthius GAA. Dosimetry in isolation perfusion of the limbs by assessments of perfused tissue volume and grading of toxic tissue reactions. Eur J Cancer Clin Oncol 1982; 18: 905-910.), to a maximum dose of 150 mg.

• 13 mg/l perfused upper limb volume
• 10 mg/l perfused lower limb volume

Paediatric population

The safety and efficacy of Beromun in children under 18 years have not been established. No data are available.

Method of administration

Precautions to be taken before handling or administering the medicinal product

When preparing and handling Beromun solutions, the use of gloves is recommended. If Beromun dry powder or reconstituted solution should come into contact with the skin or mucous membranes, they should be washed thoroughly with water.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Beromun should be administered by mild hyperthermic ILP. The perfusion circuit (roller pump, oxygenator with integrated reservoir, heat exchanger, connecting tubing) should be prepared prior to surgery and primed with 700 to 800 ml of perfusate, with haematocrit of 0.25 to 0.30.

Perfusion level should be chosen to adequately encompass affected tissue (external iliac, common femoral, femoro-popliteal, popliteal, axillary and brachial being accepted routes) and catheters introduced. External heat loss from the limb should be prevented by application of thermal blankets and limb temperature continuously monitored by thermistor probes inserted into subcutaneous tissue and muscle. Hand and foot, if not affected, should be protected by Esmarch (expulsion) bandages. A tourniquet should be applied to the proximal limb.

After connection of the limb to the isolated circuit, flow rate should be adjusted to 35 to 40 ml/litre limb volume/minute and leakage from limb to systemic circulation checked using a radioactive tracer technique (see section 4.4). Adjustment of flow rate and tourniquet may be required to ensure leakage from perfusion circuit to systemic circulation is stable (systemic level of radioactivity has reached a plateau) and does not exceed 10%. Beromun should only be administered if leakage is less than 10%.

Once the temperature in the distal subcutaneous tissue of the limb has reached >38°C, (but not exceeding 39°C), and pH of the perfusate is between 7.2 and 7.35, Beromun should be injected as a bolus into the arterial line of the circuit. After 30 minutes perfusion of Beromun alone, melphalan should be added as a bolus into the reservoir of the circuit, or slowly into the arterial line of the circuit. The temperature should then be increased to >39°C (but not exceeding 40°C) in two different sites of measurement in the tumour area. The duration of the perfusion including melphalan should be 60 minutes. Thus, the duration of the total perfusion should be 90 minutes.

At the end of the perfusion, the perfusate should be collected into the reservoir while washout fluid is added simultaneously to the circuit and circulated at the same flow rate of 35 to 40 ml/litre limb volume/minute. Washout should be continued until the colour of the perfusate is clear pink, transparent (see section 4.4).

Surgical resection of the tumour remnant should be undertaken whenever possible. When necessary a second ILP can be considered 6-8 weeks after the first ILP (see section 4.4).

Should accidental overdose occur, ILP should be terminated immediately and the limb washed out using at least 2 litres of dextran 70 intravenous infusion or similar fluid (see also section 4.4).

If signs of systemic toxicity appear, for example fever, cardiac arrhythmias, shock/hypotension, adult respiratory distress syndrome (ARDS), general supportive measures should be employed and the patient immediately transferred to an Intensive Care Unit for monitoring. Volume expanders and vasopressors are recommended. Artificial respiratory support may be required if ARDS develops. Renal and hepatic function should be closely monitored. Haematological disorders, in particular leukopaenia, thrombocytopaenia and clotting dysfunction, might be expected.

There is no specific antidote for tasonermin currently available. Treatment with anti-TNFα antibodies is not recommended.

Please refer to the Summary of Product Characteristics for melphalan for information on overdose of melphalan.

Shelf life: 3 years.

Reconstituted solution: Chemical and physical in-use stability has been demonstrated for up to 48 hours at 25°C.

From a microbiological point of view, the reconstituted 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 24 hours at 2 to 8°C, unless reconstitution has taken place in controlled and validated aseptic conditions.

Store in a refrigerator (2°C-8°C).

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Powder vial: Type I glass vial with chlorobutyl rubber stopper and sealed with aluminium flip-off cap.

Each pack contains 4 vials.

Instructions for reconstitution

The content of one vial of Beromun powder should be reconstituted with 5.3 ml sterile 0.9% sodium chloride solution for injection. A homogeneous solution will be obtained by shaking gently. The solution of the reconstituted product should be inspected visually for particulate matter prior to administration. The solution has a clear to light yellow colour. The formulation does not contain a preservative and is for single use only. Once opened, the content of a vial should normally be used immediately (see section 6.3). For instructions on administration, see section 4.2.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.