Beromun · 4.1 Therapeutic indications · 1

HOS-083754 · has-adverse-reaction-information · PDF-Seite 7

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 7  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 Gener

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HOS-083750 · has-contraindication-information · PDF-Seite 3

Contraindications to Beromun ILP, subdivided by components of the procedure, are: Contraindications to Beromun: Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Significant cardiovascular disease, e.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. 3 A recent history of, or active peptic ulcer. Severe ascites. Significant haematological dysfunction, e.g. leucocytes < 2.5 x 109/l, haemoglobin < 9 g/dl, platelets < 60 x 109/l, haemorrhagic diathesis or active bleeding disorder. Significant renal dysfunction, e.g. nephrotic syndrome, serum creatinine > 150 µmol/l, or creatinine clearance of < 50 ml/min. Significant hepatic dysfunction, e.g. > 2 x upper limits of normal levels of aspartate aminotransferase, alanine aminotransferase or alkaline phosphatase; or bilirubin levels > 1.25 x upper limits of normal. Hypercalcaemia > 12 mg/dl (2.99 mmol/l). Patients with contraindications to the use of vasopressor substances. Patients with contraindications to the use of anticoagulants. Simultaneous treatment with cardiotoxic substances (e.g. anthracyclines). Pregnancy and lactation (see section 4.6). 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.

HOS-083749 · has-indication-information · PDF-Seite 2

Beromun is indicated in adults. as an adjunct to surgery for subsequent removal of the tumour so as to prevent or delay amputation, or in the palliative situation, for irresectable soft tissue sarcoma of the limbs, used in combination with melphalan via mild hyperthermic isolated limb perfusion (ILP).

HOS-083752 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed. Beromun has been co-administered with interferon-gamma in the ILP setting but no added value has been demonstrated. The addition of interferon-gamma to the tasonermin perfusate seems not to be associated with significant increases in endogenous production of tasonermin or other inflammatory cytokines as shown in patients with severe trauma. Clinical data however indicate that the overall incidence of adverse events is increased if patients are simultaneously exposed to tasonermin and interferon-gamma. Combinations with cardiotoxic substances (e.g. anthracyclines) should be avoided because it is possible that tasonermin could enhance cardiotoxicity, as has been observed in preclinical 13-week toxicological investigations (see section 4.4). A number of therapeutic measures are routinely used during the ILP and in the immediate post-operative period. These include standard anaesthetic agents, analgesics, antipyretics, intravenous fluids, anticoagulants and vasopressor agents. There is no evidence that any of these agents counteracts the pharmacodynamic effects of tasonermin. No significant interactions have so far been noted, but caution should be exercised (see section 4.4). Concurrent administration of agents likely to cause significant hypotension is not recommended (see section 4.4). The Summary of Product Characteristics for melphalan should be consulted for information on the interactions of melphalan. 6

HOS-083753 · has-pregnancy-information · PDF-Seite 7

Pregnancy There are no adequate data from the use of tasonermin in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal development and postnatal development (see section 5.3). The potential risk for humans is unknown. Beromun is contraindicated in pregnancy (see section 4.3). Breastfeeding It is not known whether tasonermin is excreted in human milk. Because of the unknown risk to the infant, breast-feeding is contraindicated within 7 days of ILP (see section 4.3). Fertility No data on the possible effect of this medicinal product on male and female fertility are available.

HOS-083751 · has-warning-information · PDF-Seite 4

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. 4 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. In addition, as the clinical situation dictates, a vasopressor agent, e.g. dopamine, can be considered for administration during the ILP procedure, as well as in the post-operative period. In the event of severe shock before the end of the ILP, the limb perfusion should be discontinued and appropriate therapy administered. In order to minimise the risk of leakage of the perfusate into the systemic circulation, the perfusion flow rate shou

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