BEROMUN 1mg / 5ml powder + solvent infusion solution medication leaflet

Beromun 1 mg powder for solution for infusion

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.

Each vial contains 20.12 mg (0.87 mmol) sodium. After reconstitution in 0.9 % physiological sodiumchloride solution the amount is 37.82 mg (1.64 mmol) sodium.

For the full list of excipients, see section 6.1.

Powder for solution for infusion (powder for infusion).

The powder is white to off-white.

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

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

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 isolationperfusion 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 volume10 mg/l perfused lower limb volume

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

When preparing and handling Beromun solutions, the use of gloves is recommended. If Beromun drypowder or reconstituted solution should come into contact with the skin or mucous membranes, theyshould 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 tosurgery 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, commonfemoral, femoro-popliteal, popliteal, axillary and brachial being accepted routes) and cathetersintroduced. External heat loss from the limb should be prevented by application of thermal blanketsand limb temperature continuously monitored by thermistor probes inserted into subcutaneous tissueand muscle. Hand and foot, if not affected, should be protected by Esmarch (expulsion) bandages. Atourniquet 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/litrelimb volume/minute and leakage from limb to systemic circulation checked using a radioactive tracertechnique (see section 4.4). Adjustment of flow rate and tourniquet may be required to ensure leakagefrom perfusion circuit to systemic circulation is stable (systemic level of radioactivity has reached aplateau) 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 notexceeding 39°C), and pH of the perfusate is between 7.2 and 7.35, Beromun should be injected as abolus into the arterial line of the circuit. After 30 minutes perfusion of Beromun alone, melphalanshould 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 ofmeasurement in the tumour area. The duration of the perfusion including melphalan should be 60minutes. 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 isadded simultaneously to the circuit and circulated at the same flow rate of 35 to 40 ml/litre limbvolume/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 asecond ILP can be considered 6-8 weeks after the first ILP (see section 4.4).

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 periodprior to treatment, venous thrombosis, occlusive peripheral arterial disease, recent pulmonaryembolism.

Severe pulmonary dysfunction.

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 creatinineclearance 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 highlydependent on tumour associated blood vessels. This can be clarified by an arteriogram.

Pregnancy and lactation.

ILP should be undertaken in specialised centres by surgical teams experienced in the management oflimb sarcomas and ILP procedure, with an intensive care unit readily available and with the facilitiesfor continuous monitoring for medicinal product leakage into the systemic circulation. Beromun mustnot be administered systemically.

Please refer to the Summary of Product Characteristics of melphalan prior to commencing an ILPprocedure.

Induction of general anaesthesia and subsequent mechanical ventilation should be applied according tostandard methods. It is important to maintain a constant level of anaesthesia in order to prevent largefluctuations in systemic blood pressure, which can affect leakage between systemic circulation andperfusion circuit.

During the ILP, central venous pressure and arterial pressure monitoring is strongly recommended.

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

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

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

Additional resuscitation fluids (crystalloid and colloid solutions) should be available for volumeexpansion in case of a significant fall in blood pressure. Colloids and hydroxyethyl starch fluids arepreferred, as they are less likely to leak out of the vascular system. In addition, as the clinical situationdictates, a vasopressor agent, e.g. dopamine, can be considered for administration during the ILPprocedure, 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 perfusionflow rate should not exceed 40 ml/litre limb volume/minute. Potential leakage should be measured byradioactively labelled albumin or erythrocytes injected into the perfusion circuit, with appropriatemeasures for continuous monitoring of radioactivity leakage into the systemic circulation. Adjustmentof flow rate and tourniquet may be required to ensure leakage is stable (systemic level of radioactivityhas reached a plateau) and does not exceed 10%. The perfusion should be terminated if the cumulativeleakage into the systemic circulation is > 10%. In such cases, a standard wash-out procedure shouldfollow, 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 70intravenous infusion or similar fluid. After lower limb perfusion, 3 to 6 litres should be used, and afterupper 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 asbrief as possible (20 minutes maximum).

Surgical resection of the tumour remnant should be undertaken whenever possible. When necessary asecond 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 undesirableeffects are to be expected. Doses of up to 6 mg of other TNFα preparations have been administeredvia 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 ispossible that tasonermin could enhance cardiotoxicity, as has been observed in preclinical 13-weektoxicological investigations. Concurrent administration of agents likely to cause significanthypotension is not recommended (see section 4.5).

A number of therapeutic measures are routinely used during the ILP and in the immediatepost-operative period. These include standard anaesthetic agents, analgesics, antipyretics, intravenousfluids, anticoagulants and vasopressor agents. There is no evidence that any of these agentscounteracts the pharmacodynamic effects of tasonermin. No significant interactions have so far beennoted, but caution should be exercised (see section 4.5).

If signs of systemic toxicity appear for example fever, cardiac arrhythmias, shock/hypotension, adultrespiratory distress syndrome (ARDS), general supportive measures should be employed and thepatient immediately transferred to an Intensive Care Unit for monitoring. Volume expanders andvasopressors are recommended. Artificial respiratory support may be required if ARDS develops.

Renal and hepatic function should be closely monitored. Haematological disorders, in particularleukopaenia, thrombocytopaenia and clotting dysfunction, might be expected.

Cases of compartment syndrome characterised by pain, swelling and neurological symptoms, as wellas 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 theclinical 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 increasedmyoglobin levels in plasma and urine.

The reconstituted medicinal product contains up to 151.27 mg (6.58 mmol) sodium per recommendeddose. 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.

No interaction studies have been performed.

Beromun has been co-administered with interferon-gamma in the ILP setting but no added value hasbeen demonstrated. The addition of interferon-gamma to the tasonermin perfusate seems not to beassociated with significant increases in endogenous production of tasonermin or other inflammatorycytokines as shown in patients with severe trauma. Clinical data however indicate that the overallincidence of adverse events is increased if patients are simultaneously exposed to tasonermin andinterferon-gamma.

Combinations with cardiotoxic substances (e.g. anthracyclines) should be avoided because it ispossible that tasonermin could enhance cardiotoxicity, as has been observed in preclinical 13-weektoxicological investigations (see section 4.4).

A number of therapeutic measures are routinely used during the ILP and in the immediatepost-operative period. These include standard anaesthetic agents, analgesics, antipyretics, intravenousfluids, anticoagulants and vasopressor agents. There is no evidence that any of these agentscounteracts the pharmacodynamic effects of tasonermin. No significant interactions have so far beennoted, but caution should be exercised (see section 4.4).

Concurrent administration of agents likely to cause significant hypotension is not recommended (seesection 4.4).

The Summary of Product Characteristics for melphalan should be consulted for information on theinteractions of melphalan.

There are no adequate data from the use of tasonermin in pregnant women. Animal studies areinsufficient 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).

It is not known whether tasonermin is excreted in human milk. Because of the unknown risk to theinfant, breast-feeding is contraindicated within 7 days of ILP (see section 4.3).

No data on the possible effect of this medicinal product on male and female fertility are available.

Not relevant.

Undesirable effects may be related to Beromun, to melphalan, or to the ILP procedure and associatedmeasures, 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 mildconstitutional reactions and toxic effects on different organ systems.

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 (≥1/10,000to <1/1,000).

Common: Infection, wound infection

Uncommon: Sepsis

Common: Leukopenia, thrombocytopenia

Common: Hypersensitivity reaction

Common: Nerve injury, peripheral neurotoxicity, altered state of consciouness,headache

Very common: Arrhythmia

Common: Cardiac failure

Common: Venous thrombosis, arterial thrombosis, shock, hypotension

Uncommon: Peripheral arterial occlusive disease

Common: Adult respiratory distress syndrome

Uncommon: Pulmonary oedema

Very common: Nausea, vomiting

Common: Diarrhoea, constipation

Uncommon: Abdominal pain upper, gastritis erosive

Very common: Hepatotoxicity

Very common: Skin reaction

Common: Skin necrosis, oedema peripheral

Uncommon: Onychomadesis (loss of nails)

Common: Compartment syndrome, myalgia

Common: Proteinuria

Uncommon: Renal failure acute

Very common: Fever, chills, pain, fatigue

Common: Night sweats

Uncommon: Blood creatinine increased

Surgical and medical procedures

Common: Extremity necrosis, severe enough to warrant amputation

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 inpatients several years after ILP, predominantly in patients presenting with established cardiovascularrisk factors, or who had undergone additional irradiation therapy of the concerned limb.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Should accidental overdose occur, ILP should be terminated immediately and the limb washed outusing 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, adultrespiratory distress syndrome (ARDS), general supportive measures should be employed and thepatient immediately transferred to an Intensive Care Unit for monitoring. Volume expanders andvasopressors are recommended. Artificial respiratory support may be required if ARDS develops.

Renal and hepatic function should be closely monitored. Haematological disorders, in particularleukopaenia, thrombocytopaenia and clotting dysfunction, might be expected.

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

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

Pharmacotherapeutic group: Other immunostimulants, ATC code: L03AX11

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 avariety of tumour cell lines of different histogenesis.

Direct effects on tumour vasculature: Tasonermin affects the morphology and reduces proliferation ofendothelial cells and modifies expression of specific cell surface and secretory proteins (includingadhesion molecules and proteins modulating coagulation, interleukins and haematopoietic growthfactors). 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 tumourby lymphocytes, monocytes, and granulocytes. The reason for the differential sensitivity of the tumourvasculature (high) versus normal vasculature (low) are currently unknown.

Indirect and direct immunomodulation: Tasonermin has profound effects on cellular components ofthe immune system. Proliferation of activated B- and T-lymphocytes, development of cytotoxic

T-cells and immunoglobulin-secreting cells is enhanced, monocytes/macrophages are activated forkilling of tumour cells, granulocytes are activated to display enhanced phagocytic activity, respiratoryburst 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 lowmolecular weight mediators (prostaglandins, platelet activating factor). Several lines of evidencesuggest that these immunomodulatory activities are of relevance for the antitumour effects; e.g. theantitumour activities of tasonermin are much less pronounced in immunodeficient animals. Further,animals that reject experimental tumours following tasonermin treatment may develop specificimmunity for this tumour cell type.

Tasonermin has been shown to be active in the classic assay for tumour necrosis factor, producinghaemorrhagic necrosis of tumour nodules in murine syngeneic and human xenogeneic tumour systemsafter 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 observedhuman maximum tolerated dose.

The loco-regional application of Beromun, along with melphalan, has been shown to be highlyeffective for local control of irresectable soft tissue sarcomas of the limbs. However, the treatment isspecifically a loco-regional treatment and is not expected to influence survival. A matched-pairsurvival analysis of patients treated by Beromun and melphalan ILP as compared to a historicalcontrol failed to demonstrate any survival difference (p=0.5).

Systemic pharmacokinetics

The systemic pharmacokinetic information on tasonermin is sparse. A dose-dependency has beenobserved as indicated by a decrease in clearance and an increase in half-life at increasing doses. Theterminal 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. Dataobtained from 51 ILP patients demonstrated maximum concentrations of tasonermin in the perfusioncircuit are reached 30 min after the onset of ILP and range between 3000 and 4000 ng/ml. Underconditions of less than 2% systemic leakage (observed in 38 of 51 patients), maximum systemiccirculation concentrations of tasonermin were reached 5 min after the start of ILP and areapproximately 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 tasonerminwere still at least ten times lower than in the perfusion circuit.

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 weightgain as well as alterations in the function of liver and kidneys were the main adverse effects observedon repeated tasonermin administration. The haematological changes included anaemia, increasedhaematocrit and increased or decreased leukocytes and platelets depending upon species and treatmentduration. The circulatory changes included decreased blood pressure and, in some studies, increasedheart rate and decreased contractility. The synthesis capacity of the liver was lowered as indicated byincreased liver enzymes. Altered renal function comprised increased water and sodium excretion aswell as increased urea and creatinine. No NOTEL (No Observed Toxic Effect Level) could beestablished in the preclinical studies with the exception of a 7-day administration of 0.1 µg/kg inmonkeys. The changes observed at the low dose of the 13-week studies can be classified as minimaland fully reversible.

Tasonermin does not cross the intact blood-brain barrier to a significant extent in mice. In the Rhesusmonkey, whole body radiography following administration of radiolabelled tasonermin indicated nospecific 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 anon-specific, non-saturable excretion via glomerular filtration in the kidney. A second specific andsaturable elimination mechanism involving tasonermin receptors seems likely.

No evidence has been found of any mutagenic effect, neither in vivo nor in vitro. No reproductiontoxicity or carcinogenicity studies were performed due to testing being inappropriate as the intendedclinical 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 ofhealthy rats using different doses in the same tasonermin concentration as in the clinical situation inthe human. Except for slight aggravation of ischaemic effects in higher doses, standard histologicalexaminations of the skin, muscle, bone, nerves and vessels revealed no difference in findings betweentasonermin-treated and control animals. No late detrimental effects of tasonermin were seen.

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dodecahydrate

Human serum albumin.

At ILP, no incompatibilities with other constituents of the perfusate, with hyperthermia or with themembrane oxygenator and the silicone tubing are known. Perfusate samples of several ILPs showedplateau levels of tasonermin (as measured by ELISA) up to 100 minutes after start of perfusion, withno decay attributable to degradation.

Please refer to the Summary of Product Characteristics for melphalan for details regardingincompatabilities with melphalan.

3 years

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 notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2 to 8 °C, unless reconstitution has taken place incontrolled 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.

The content of one vial of Beromun powder should be reconstituted with 5.3 ml sterile 0.9% sodiumchloride solution for injection. A homogeneous solution will be obtained by shaking gently. Thesolution of the reconstituted product should be inspected visually for particulate matter prior toadministration. 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 ofa vial should normally be used immediately (see section 6.3). For instructions on administration, seesection 4.2.

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

BELPHARMA s.a.2, Rue Albert 1er

L-1117 Luxembourg

Grand Duchy of Luxembourg

EU/1/99/097/001

Date of first authorisation: 13 April 1999

Date of latest renewal: 13 April 2009

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu