Beromun

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Beromun 1 mg powder for solution for infusion 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each vial contains 1 mg tasonermin*, corresponding to 3.0-6.0 x 107 IU (International Units). 
 
*tumor necrosis factor alfa-1a (TNFα-1a) produced by recombinant DNA technology in E. coli. 
 
Excipient(s) with known effect:  
Each vial contains 20.12 mg (0.87 mmol) sodium. After reconstitution in 0.9 % physiological sodium 
chloride solution the amount is 37.82 mg (1.64 mmol) sodium. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Powder for solution for infusion (powder for infusion). 
 
The powder is white to off-white. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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). 
 
4.2 Posology and method of administration 
 
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. 
 



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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). 
 
4.3 Contraindications 
 
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. 
 



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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. 
 
4.4 Special warnings and precautions for use 
 
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. 
 



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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 should not exceed 40 ml/litre limb volume/minute. Potential leakage should be measured by 
radioactively labelled albumin or erythrocytes injected into the perfusion circuit, with appropriate 
measures for continuous monitoring of radioactivity leakage into the systemic circulation. Adjustment 
of flow rate and tourniquet may be required to ensure leakage is stable (systemic level of radioactivity 
has reached a plateau) and does not exceed 10%. The perfusion should be terminated if the cumulative 
leakage into the systemic circulation is > 10%. In such cases, a standard wash-out procedure should 
follow, using at least 2 litres of dextran 70 intravenous infusion or similar fluid. 
 
Following the ILP, a standard wash-out procedure should always be employed, using dextran 70 
intravenous infusion or similar fluid. After lower limb perfusion, 3 to 6 litres should be used, and after 
upper limb perfusion, 1 to 2 litres. Popliteal and brachial perfusions may not need more than 1 litre. 
Wash-out should continue until a clear (pink, transparent) venous outflow is obtained. 
 
Measures should be taken to ensure that the periods of interrupted oxygen supply to the limb are as 
brief as possible (20 minutes maximum). 
 
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. 
 
If a second ILP is indicated, physicians should take into account the leakage rate of the previous ILP. 
 
The maximum tolerated dose (MTD) of tasonermin for ILP is 4 mg, which is 10 times the systemic 
MTD. Therefore, whenever there is significant systemic leakage of tasonermin, serious undesirable 
effects are to be expected. Doses of up to 6 mg of other TNFα preparations have been administered 
via ILP, but this dose was found to be unacceptable in terms of loco-regional toxicity.  
 
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. Concurrent administration of agents likely to cause significant 
hypotension is not recommended (see section 4.5).  
 



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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 4.5).  
 
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. 
 
Cases of compartment syndrome characterised by pain, swelling and neurological symptoms, as well 
as muscle damage affecting the perfused limb have been observed in isolated patients treated with 
Beromun. Therefore patients should be monitored during the first three days after the ILP. In case the 
clinical diagnosis of compartment syndrome is made the following treatment should be considered:  
- Fasciotomy of all muscle compartments of the limb affected, 
- Forced diuresis and alkalinisation of the urine, if a muscle damage occurs with increased 

myoglobin levels in plasma and urine. 
 
The reconstituted medicinal product contains up to 151.27 mg (6.58 mmol) sodium per recommended 
dose. To be taken into consideration by patients on a controlled sodium diet. 
 
The container of this medicinal product contains latex rubber. May cause severe allergic reactions. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. 
 



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4.6 Fertility, pregnancy and lactation 
 
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. 
 
4.7 Effects on ability to drive and use machines 
 
Not relevant. 
 
4.8 Undesirable effects 
 
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 



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 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. 
 
Late onset of peripheral arterial occlusive disease (PAOD) of the lower limbs has been reported in 
patients several years after ILP, predominantly in patients presenting with established cardiovascular 
risk factors, or who had undergone additional irradiation therapy of the concerned limb. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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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. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other immunostimulants, ATC code: L03AX11 
 
Mechanism of action 
In vivo antitumour activity is probably based on direct and indirect effects: 
 
Direct inhibition of tumour cell proliferation: Tasonermin is cytotoxic or cytostatic in vitro for a 
variety of tumour cell lines of different histogenesis. 
 
Direct effects on tumour vasculature: Tasonermin affects the morphology and reduces proliferation of 
endothelial cells and modifies expression of specific cell surface and secretory proteins (including 
adhesion molecules and proteins modulating coagulation, interleukins and haematopoietic growth 
factors). These changes in turn lead to a procoagulant state, resulting in microvascular thrombosis. 
Further, adherence and extravasation of leukocytes is increased, leading to infiltration of the tumour 
by lymphocytes, monocytes, and granulocytes. The reason for the differential sensitivity of the tumour 
vasculature (high) versus normal vasculature (low) are currently unknown. 
 
Indirect and direct immunomodulation: Tasonermin has profound effects on cellular components of 
the immune system. Proliferation of activated B- and T-lymphocytes, development of cytotoxic 
T-cells and immunoglobulin-secreting cells is enhanced, monocytes/macrophages are activated for 
killing of tumour cells, granulocytes are activated to display enhanced phagocytic activity, respiratory 
burst and degranulation, and adherence to endothelium. Further, in addition to its direct effects, 
tasonermin modulates immune responses by inducing production of cytokines as well as low 
molecular weight mediators (prostaglandins, platelet activating factor). Several lines of evidence 
suggest that these immunomodulatory activities are of relevance for the antitumour effects; e.g. the 
antitumour activities of tasonermin are much less pronounced in immunodeficient animals. Further, 
animals that reject experimental tumours following tasonermin treatment may develop specific 
immunity for this tumour cell type. 
 
Pharmacodynamic effects 
Tasonermin has been shown to be active in the classic assay for tumour necrosis factor, producing 
haemorrhagic necrosis of tumour nodules in murine syngeneic and human xenogeneic tumour systems 
after local or systemic injection. The systemic application of tasonermin is limited by its toxic effects, 
the effective dose predicted from preclinical studies being substantially higher than the observed 
human maximum tolerated dose.  
 
Clinical efficacy 
The loco-regional application of Beromun, along with melphalan, has been shown to be highly 
effective for local control of irresectable soft tissue sarcomas of the limbs. However, the treatment is 
specifically a loco-regional treatment and is not expected to influence survival. A matched-pair 
survival analysis of patients treated by Beromun and melphalan ILP as compared to a historical 
control failed to demonstrate any survival difference (p=0.5). 



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5.2 Pharmacokinetic properties 
 
Systemic pharmacokinetics 
The systemic pharmacokinetic information on tasonermin is sparse. A dose-dependency has been 
observed as indicated by a decrease in clearance and an increase in half-life at increasing doses. The 
terminal half-life at the maximum tolerated intravenous dose (150 µg/m2) was 15-30 min. 
 
Pharmacokinetics in ILP 
ILP allows the administration of high and fairly stable concentrations of tasonermin to the limb. Data 
obtained from 51 ILP patients demonstrated maximum concentrations of tasonermin in the perfusion 
circuit are reached 30 min after the onset of ILP and range between 3000 and 4000 ng/ml. Under 
conditions of less than 2% systemic leakage (observed in 38 of 51 patients), maximum systemic 
circulation concentrations of tasonermin were reached 5 min after the start of ILP and are 
approximately 200 times less than in the perfusion circuit. Under conditions of greater than 2 % 
systemic leakage (observed in 13 of 51 patients) maximum systemic concentrations of tasonermin 
were still at least ten times lower than in the perfusion circuit.  
 
5.3 Preclinical safety data 
 
The toxicological profile of tasonermin has been investigated in preclinical studies using mice, rats, 
rabbits, dogs and monkeys. Haematological and circulatory changes, decreased well-being and weight 
gain as well as alterations in the function of liver and kidneys were the main adverse effects observed 
on repeated tasonermin administration. The haematological changes included anaemia, increased 
haematocrit and increased or decreased leukocytes and platelets depending upon species and treatment 
duration. The circulatory changes included decreased blood pressure and, in some studies, increased 
heart rate and decreased contractility. The synthesis capacity of the liver was lowered as indicated by 
increased liver enzymes. Altered renal function comprised increased water and sodium excretion as 
well as increased urea and creatinine. No NOTEL (No Observed Toxic Effect Level) could be 
established in the preclinical studies with the exception of a 7-day administration of 0.1 µg/kg in 
monkeys. The changes observed at the low dose of the 13-week studies can be classified as minimal 
and fully reversible.  
 
Tasonermin does not cross the intact blood-brain barrier to a significant extent in mice. In the Rhesus 
monkey, whole body radiography following administration of radiolabelled tasonermin indicated no 
specific distribution pattern. Tasonermin did not cross the placenta or pass into necrotic tumour. In the 
Rhesus monkey, pharmacokinetic studies following intravenous injection of tasonermin indicated a 
non-specific, non-saturable excretion via glomerular filtration in the kidney. A second specific and 
saturable elimination mechanism involving tasonermin receptors seems likely. 
 
No evidence has been found of any mutagenic effect, neither in vivo nor in vitro. No reproduction 
toxicity or carcinogenicity studies were performed due to testing being inappropriate as the intended 
clinical use of Beromun is in ILP for soft tissue sarcoma treatment.  
 
To cover the intended clinical use of Beromun, ILP experiments were performed in hind legs of 
healthy rats using different doses in the same tasonermin concentration as in the clinical situation in 
the human. Except for slight aggravation of ischaemic effects in higher doses, standard histological 
examinations of the skin, muscle, bone, nerves and vessels revealed no difference in findings between 
tasonermin-treated and control animals. No late detrimental effects of tasonermin were seen. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients  
 
Sodium dihydrogen phosphate dihydrate 
Disodium phosphate dodecahydrate 



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Human serum albumin.  
 
6.2 Incompatibilities 
 
At ILP, no incompatibilities with other constituents of the perfusate, with hyperthermia or with the 
membrane oxygenator and the silicone tubing are known. Perfusate samples of several ILPs showed 
plateau levels of tasonermin (as measured by ELISA) up to 100 minutes after start of perfusion, with 
no decay attributable to degradation. 
 
Please refer to the Summary of Product Characteristics for melphalan for details regarding 
incompatabilities with melphalan. 
 
6.3 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. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C - 8°C). 
 
For storage conditions after reconstitution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Powder vial 
Type I glass vial with chlorobutyl rubber stopper and sealed with aluminium flip-off cap. 
 
Each pack contains 4 vials. 
 
6.6 Special precautions for disposal and other handling 
 
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. 
 
 



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7. MARKETING AUTHORISATION HOLDER 
 
BELPHARMA s.a. 
2, Rue Albert 1er  
L-1117 Luxembourg 
Grand Duchy of Luxembourg 
 
 
8. MARKETING AUTHORISATION NUMBER 
 
EU/1/99/097/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 April 1999 
Date of latest renewal: 13 April 2009 
 
 
10. DATE OF REVISION OF THE TEXT  
 
 
Detailed information on this product is available on the website of the European Medicines Agency  
http://www.ema.europa.eu 
 
 

http://www.emea.europa.eu/


13 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 
SUBSTANCE AND MANUFACTURER (S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE 

SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 



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A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 
MANUFACTURER (S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Boehringer Ingelheim RCV GmbH & Co KG 
Dr. Boehringer Gasse 5-11  
1121 Vienna 
Austria 
 
Name and address of the manufacturer responsible for batch release 
 
Eumedica NV 
Chemin de Nauwelette 1 
B-7170 Manage 
Belgium 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports  
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal 
 
 
D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
Not applicable 
 



15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



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A. LABELLING 



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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Beromun 1 mg powder for solution for infusion 
Tasonermin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each vial contains 1 mg tasonermin, corresponding to 3.0-6.0 x 107 IU. 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium dihydrogen phosphate dihydrate, disodium phosphate dodecahydrate, human serum albumin 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Powder for solution for infusion 
 
4 vials of powder for solution for infusion 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
For administration by ILP 
Intraarterial use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
For single use only. Upon reconstitution the product should be used immediately. 
 
 



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9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BELPHARMA s.a. 
2, Rue Albert 1er  
L-1117 Luxembourg 
Grand Duchy of Luxembourg 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/99/097/001 
 
 
13. BATCH NUMBER 
 
Batch  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: {number} [product code] 
SN: {number} [serial number] 
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 
 
 



19 

 
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL LABEL FOR BEROMUN 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Beromun 1 mg powder for infusion 
Tasonermin 
Intraarterial use 
 
 
2. METHOD OF ADMINISTRATION 
 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Batch  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
1 mg 
 
 
6. OTHER 
 
 



20 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 



21 

Package leaflet: Information for the user 
 

Beromun 1 mg powder for solution for infusion 
Tasonermin 

 
Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor. 
- If you get any side effects , talk to your doctor. This includes any possible side effects not 

listed in this leaflet. 
 
 
What is in this leaflet: 
1. What Beromun is and what it is used for 
2. What you need to know before you use Beromun 
3. How to use Beromun 
4. Possible side effects 
5. How to store Beromun 
6. Contents of the pack and other information 
 
 
1. What Beromun is and what it is used for 
  
Beromun contains the active substance tasonermin (tumor necrosis factor alfa-1a), produced by 
recombinant DNA technology. It belongs to a class of medicines known as immunostimulants, which 
help your body’s immune system fight cancer cells. 
 
Beromun is used, together with melphalan containing medicine, for the treatment of soft tissue 
sarcoma of the arms and legs. By reducing the size of the tumour, the treatment is intended to facilitate 
the removal of the tumor by surgery or to prevent severe damage to the surrounding healthy tissue and 
thus to delay or prevent the need for arm or leg amputation.  
 
 
2. What you need to know before you use Beromun 
 
Do not use Beromun 
- if you are allergic to tasonermin or any of the other ingredients of this medicine (listed in 

section 6). 
- if you have significant heart problems 
- if you have severe lung disease 
- if you have or have recently had a stomach ulcer 
- if you have too low numbers of blood cells or bleeding problems 
- if you have moderate to severe liver or kidney disease 
- if you cannot use vasopressors (used to increase low blood pressure), anticoagulants (used to 

prevent blood clotting) or radioactive tracers 
- if you are also using medicines with heart toxicity  
- if you have raised levels of calcium in your blood 
- if you have certain infections which do not respond to antibiotics 
- if you have severe swelling of the affected arm or leg due to local fluid build-up, or severe fluid 

build-up in the abdomen 
- if you are pregnant or planning to become pregnant. 
- if you are breast-feeding, you must stop for at least seven days after receiving Beromun 
 
Warnings and precautions  
Beromun will be administered by a doctor who is experienced and skilled in isolated limb perfusion 
(ILP). This technique ensures that Beromun is kept within the affected arm or leg. It is important that 



22 

it does not reach other parts of your body, because this so-called systemic leakage could cause serious 
side effects on the main organs of the body.  
 
During the IPL and the seven to ten day period afterwards you will need to stay in hospital, your 
doctor will carefully monitor your blood pressure, circulation and any side effects. You may have to 
stay in an intensive care unit (ICU) directly after the ILP for a short time. 
 
A condition called “compartment syndrome” may develop within the first three days after Beromun 
administration. Symptoms of muscle damage at the perfused limb include pain, swelling, as well as 
neurological symptoms (e. g. paraesthesia, paralysis), all of which should be reported immediately to 
the attending doctor. 
 
Other medicines and Beromun 
Tell your doctor if you are using,  have recently used or might use any other medicines. In particular, 
you should tell your doctor if you are using medicines to lower blood pressure (to treat hypertension). 
 
For ILP, you will also receive other medicines to control pain, fever, blood pressure and blood 
clotting, as well as general anaesthesia. 
 
Pregnancy and breast-feeding 
You must not use Beromun if you are pregnant. 
You must not breast-feed for at least seven days after treatment with Beromun. 
 
Driving and using machines 
Not relevant 
 
Beromun contains sodium 
The reconstituted medicinal product contains up to 151.27 mg (6.58 mmol) sodium per recommended 
dose. To be taken into consideration by patients on a controlled sodium diet. 
 
The container contains latex rubber 
The container of this medicinal product contains latex rubber. May cause severe allergic reactions. 
 
 
3. How to use Beromun 
 
Beromun will be administered by isolated limb perfusion (ILP), together with the anti-tumour agent 
melphalan. This will occur whilst you are unconscious, under the influence of a general anaesthetic. 
 
The blood flow to and from your affected limb will be stopped using a tourniquet. Blood, supplied 
with oxygen by a heart and lung machine, is pumped into your affected limb via a catheter in the main 
artery, while it is drained (pumped out) from the main vein. Beromun and then melphalan are injected 
into this circuit, over a total of 90 minutes the affected limb will be exposed to Beromun. 
 
The recommended dose of Beromun depends on the affected limb, usually 3 mg for the arm and 4 mg 
for the leg. Beromun powder has to be dissolved before use. The resulting solution will be 
administered into an artery in your affected arm or leg by ILP for an initial period of 30 minutes.  
After that, melphalan will be added and the ILP continued for another 60 minutes.  
Finally, your limb will be washed out to remove the rest of Beromun and melphalan. 
 
ILP allows that tumour cells in your limb can be exposed to a very high dose of Beromun and 
melphalan, enhancing their anti-tumour effect, but without reaching the rest of the body, where they 
could cause serious side effects.  
 
You will usually not receive a second ILP with Beromun. If you do, this will not be until at least six 
weeks after your first ILP. 
 



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If you use more Beromun than you should 
As Beromun is always administered by experienced and qualified hospital doctors, accidental 
overdose is extremely unlikely. However, should this occur, your doctor will immediately wash out 
your affected limb to remove Beromun, and the ILP will be stopped. If there is any risk of serious side 
effects, your doctor will immediately transfer you to an intensive care unit to closely monitor you and 
start adequate treatment. 
 
If there is significant systemic leakage of Beromun 
If more than 10% of your Beromun dose reaches the main part of your body, your doctor will take 
similar measures as in the case of overdose.  
 
If you have any further questions on the use of this product, ask your doctor. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Side effects may be caused by Beromun, melphalan, the ILP technique or a combination of these 
factors. Some of the side effects can be serious, particularly if Beromun reaches other parts of your 
body (systemic leakage). In approximately 2% of cases, Beromun may cause tissue damage in your 
affected arm or leg which is severe enough to require amputation. If there is any risk of serious side 
effects, your doctor will immediately transfer you to an intensive care unit to closely monitor you and 
start adequate treatment. 
 
The following side effects were observed during treatment with this medicine (grouped by how likely 
they are to happen). 
 
Very common (may affect more than 1 in 10 people) 
- disturbances in your heart beat (arrhythmia) 
- feeling sick, vomiting 
- liver damage 
- blistering of the skin 
- fever (usually mild to moderate), chills 
- pain in the affected arm or leg 
- tiredness (fatigue) 
 
Common (may affect up to 1 in 10 people) 
- infections 
- local wound infections 
- reductions in numbers of certain white blood cells and platelets 
- hypersensitivity (allergic) reactions 
- nerve damage 
- decreased consciouness  
- headache 
- heart problems which can cause shortness of breath or ankle swelling 
- blood clot formation in the artery or vein of the affected arm or leg (thrombosis) 
- low blood pressure, shock 
- severe breathing problems 
- constipation, diarrhoea 
- skin necrosis (death of skin cells) in the affected arm or leg 
- swelling of the ankles, feet or fingers caused by fluid build up in the affected arm or leg 
- “compartment syndrome”, a medical condition characterised by pain, swelling and neurological 

symptoms, as well as muscle damage in the affected arm or leg 
- muscle pain 
- protein in urine 
- night sweats 



24 

- tissue necrosis (death of tissue cells) in the affected arm or leg, which is severe enough to 
require amputation 

 
Uncommon (may affect up to 1 in 100 people) 
- blood poisoning (sepsis) 
- fluid in the lungs 
- stomach ache 
- inflammation of the gastric mucosa (gastritis)  
- temporary loss of finger or toe nails of the affected arm or leg 
- kidney failure 
- blood tests showing changes in the way the kidneys are working 
- narrowing or closing of limb vessels carrying blood from the heart 
 
Reporting of side effects 
If you get any side effects talk to your doctor. This includes any possible side effects not listed in this 
leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. 
By reporting side effects you can help provide more information on the safety of this medicine. 
 
 
5. How to store Beromun 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton and vial label after EXP. 
The expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C - 8°C). Upon reconstitution the product should be used immediately. 
 
 
6. Contents of the pack and other information 
 
What Beromun contains 
- The active substance is tasonermin. Each vial contains 1 mg tasonermin. The content of one vial 

of Beromun powder should be reconstituted with 5.3 ml sterile 0.9% sodium chloride solution 
for injection  

- The other ingredients (excipient(s)) are sodium dihydrogen phosphate dihydrate, disodium 
phosphate dodecahydrate and human serum albumin. 

 
What Beromun looks like and contents of the pack 
Beromun is a white to off-white powder for solution for infusion (powder for infusion) supplied in a 
glass vial with rubber stopper and sealed with aluminium flip-off cap. 
Each pack contains 4 vials of powder. 
 
Marketing Authorisation Holder  
BELPHARMA s.a. 
2, Rue Albert 1er  
L-1117 Luxembourg 
Grand Duchy of Luxembourg 
 
Manufacturer  
Eumedica NV 
Chemin de Nauwelette 1 
B-7170 Manage 
Belgium  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


25 

For any information about this medicine, please contact the Marketing Authorisation Holder: 
 
BELPHARMA s.a. 
2, Rue Albert 1er  
L-1117 Luxembourg 
Grand Duchy of Luxembourg 
Tel : +352 27403070 
 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER (S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.  OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.  CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET