Boehringer Ingelheim Limited

Beromun 1 mg/5 ml powder and solvent for solution for infusion

Each vial contains 1 mg tasonermin*, corresponding to 3.0-6.0 x 10⁷ IU (International Units).

After reconstitution, each ml contains 0.2 mg tasonermin.

*tumor necrosis factor alfa-1a (TNFα-1a) produced by recombinant DNA technology in E. coli.

Excipients:

After reconstitution, each vial contains 19 mg (0.8 mmol) sodium.

For a full list of excipients, see section 6.1.

Powder and solvent for solution 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 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).

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 or 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).

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.

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 month period prior to treatment, venous thrombosis, occlusive peripheral arterial disease, recent pulmonary embolism.

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 creatinine clearance of < 50 ml/minute.

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.

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.

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).

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.

This medicinal product contains up to 77 mg (3.3 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.

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.

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.

Not relevant.

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).

Description of selected adverse reactions

Extremity necrosis and compartment syndrome might be severe enough to warrant amputation.

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.

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).

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 minutes.

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 minutes 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 minutes 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.

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.

Powder

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dodecahydrate

Human serum albumin.

Solvent

Sodium chloride

Water for injections.

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.

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 of the reconstituted medicinal product, see section 6.3.

Powder vial

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

Solvent ampoule

One glass ampoule contains 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection

Each pack contains 4 vials and 4 ampoules.

Instructions for reconstitution

Beromun should be reconstituted by adding 5 ml of the provided solvent for parenteral use (sodium chloride 9 mg/ml (0.9%) 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 product or waste material should be disposed of in accordance with local requirements.

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

EU/1/99/097/001

Date of first authorisation: 13 April 1999

Date of latest renewal: 13 April 2009

27.7.2011