Beromun

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. ), 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. 3 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.

6. Beromun should be administered by mild hyperthermic ILP. 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. 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 %. 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.

Summary of the safety profile Undesirable effects may be related to Beromun, to melphalan, or to the ILP procedure and associated measures, or to a combination of these factors. The most frequent adverse reactions reported in clinical trials were fever, nausea, vomiting, fatigue, arrhythmia, chills, pain, wound infection and skin reaction.

Adverse reactions are either local, affecting the limb treated with ILP, or systemic. Systemic adverse reactions include mild constitutional reactions and toxic effects on different organ systems. Tabulated summary of adverse reactions Adverse reactions have been ranked under headings of frequency using the following convention: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000).

Infections and infestations Common:

Infection, wound infection Uncommon: Sepsis Blood and lymphatic system disorders Common: Leukopenia, thrombocytopenia Immune system disorders Common: Hypersensitivity reaction Nervous system disorders Common: Nerve injury, peripheral neurotoxicity, altered state of consciouness, headache Cardiac disorders Very common: Arrhythmia Common: Cardiac failure Vascular disorders Common: Venous thrombosis, arterial thrombosis, shock, hypotension 8 Uncommon: Peripheral arterial occlusive disease Respiratory, thoracic and mediastinal disorders Common: Adult respiratory distress syndrome Uncommon: Pulmonary oedema Gastrointestinal disorders Very common: Nausea, vomiting Common: Diarrhoea, constipation Uncommon: Abdominal pain upper, gastritis erosive Hepatobiliary disorders Very common: Hepatotoxicity Skin and subcutaneous tissue disorders Very common: Skin reaction Common: Skin necrosis, oedema peripheral Uncommon: Onychomadesis (loss of nails) Musculoskeletal and connective tissue disorders Common: Compartment syndrome, myalgia Renal and urinary disorders Common: Proteinuria Uncommon: Renal failure acute General disorders and administration site conditions Very common: Fever, chills, pain, fatigue Common: Night sweats Investigations Uncommon: Blood creatinine increased Surgical and medical procedures Common: Extremity necrosis, severe enough to warrant amputation Description of selected adverse reactions Extremity necrosis and compartment syndrome might be severe enough to warrant amputation.

ILP 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.

Beromun must not be administered systemically. Please refer to the Summary of Product Characteristics of melphalan prior to commencing an ILP procedure. 5 Induction of general anaesthesia and subsequent mechanical ventilation should be applied according to standard methods.

It is important to maintain a constant level of anaesthesia in order to prevent large fluctuations in systemic blood pressure, which can affect leakage between systemic circulation and perfusion circuit. During the ILP, central venous pressure and arterial pressure monitoring is strongly recommended.

Furthermore, blood pressure, urine output and electrocardiographic monitoring should be routinely undertaken in the first 24 to 48 hours post-ILP, or longer if indicated. A Swan-Ganz catheter may be considered for monitoring pulmonary artery pressure and wedge pressure during the ILP and in the post-operative period.

Prophylaxis and treatment of fever, chills and other influenza-like symptoms associated with Beromun administration can be achieved by pre-ILP administration of paracetamol (oral or by suppository) or an alternative analgesic/antipyretic.

For the prophylaxis of shock, patients should always be maximally hydrated prior to, during and after the perfusion procedure. This is to ensure optimal haemodynamic conditions and ensure a high urinary output, especially after the perfusion, to allow for rapid clearance of any residual tasonermin.

Additional resuscitation fluids (crystalloid and colloid solutions) should be available for volume expansion in case of a significant fall in blood pressure. Colloids and hydroxyethyl starch fluids are preferred, as they are less likely to leak out of the vascular system.

1. g. congestive heart failure (New York Heart Association Class II, III or IV), severe angina pectoris, cardiac arrhythmias, myocardial infarction within a 3 months period prior to treatment, venous thrombosis, occlusive peripheral arterial disease, recent pulmonary embolism.

Severe pulmonary dysfunction. 4 A recent history of, or active peptic ulcer. Severe ascites. g. 5 x 109/l, haemoglobin < 9 g/dl, platelets < 60 x 109/l, haemorrhagic diathesis or active bleeding disorder. g. nephrotic syndrome, serum creatinine > 150 μmol/l, or creatinine clearance of < 50 ml/min.

g. 25 x upper limits of normal. 99 mmol/l). Patients with contraindications to the use of vasopressor substances. Patients with contraindications to the use of anticoagulants. g. anthracyclines). 6).

Contraindications to melphalan:

Please refer to the Summary of Product Characteristics for melphalan.

Contraindications to the ILP procedure:

Severe ascites. Severe lymphoedema of the limb. Patients with contraindications to the use of vasopressor agents. Patients with contraindications to the use of anticoagulants. Patients with contraindications to radioactive tracer monitoring.

Patients with contraindications to limb hyperthermia. Patients in whom the blood supply to the extremity distal to the tumour is suspected to be highly dependent on tumour associated blood vessels. This can be clarified by an arteriogram.

Pregnancy and lactation.