Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: BELPHARMA s.a., 2, Rue Albert 1er, L-1117, Luxembourg, Grand Duchy of Luxembourg
Contraindications to Beromun ILP, subdivided by components of the procedure, are:
Contraindications to Beromun:
Contraindications to melphalan:
Please refer to the Summary of Product Characteristics for melphalan.
Contraindications to the ILP procedure:
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:
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.
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.
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).
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).
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 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.
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).
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
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 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 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.
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.
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