Medicinal Products

BEROMUN 1 mg / 5 mL

Generic drug of the therapeutic class: Oncology and Hematology
active ingredients: Tasonermine
laboratory: Boehringer Ingelheim

Powder and solvent for solution for IV infusion
Box of 4 vials + 5 ml solvent ampoules
All forms

Indication

BEROMUN is indicated, in perfusion of the limb isolated under slight hyperthermia and in association with melphalan for the treatment of soft tissue sarcomas of the limbs:

- before surgical resection of the tumor, to avoid or delay amputation,

- palliative, for inoperable sarcomas.

Dosage BEROMUN 1 mg / 5 mL Powder and solvent for solution for infusion IV Box of 4 vials + 5 ml solvent ampoules

This treatment should be initiated in specialized centers, by surgical teams experienced in the treatment of sarcomas of members and familiar with the technique of ILP. These hospitals must have an intensive care unit and all the equipment necessary to continuously monitor and detect a passage of the drug into the systemic circulation.

Dosage

BEROMUN:

Upper limb: total dose of 3 mg, infusion of the isolated limb

Lower limb: total dose of 4 mg infusion of the isolated limb.

Melphalan:

The dose of melphalan should be calculated according to the Wieberdink method (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. J Cancer Clin Oncol 1982; 18: 905-910.), Without exceeding 150 mg.

13 mg / unit volume (in liter) of the infused upper extremity

10 mg / unit volume (in liter) of infused lower limb.

Administration mode

For instructions on reconstitution before administration, see section Special precautions for disposal and other handling .

BEROMUN should be infused into the isolated limb under mild hyperthermia. The infusion circuit (pump, oxygenator with integrated reservoir, heat exchanger, tubing) must be prepared before the operation and primed with 700 to 800 ml of perfusate, for a hematocrit of between 0.25 and 0.30.

The site of the infusion should be chosen to best circumscribe the affected areas (external iliac, femoral, femoropopliteal, popliteal, axillary and brachial can be used) and the catheter should be in place. The external heat loss of the limb must be prevented by the application of warming blankets, the temperature of the limb must be continuously monitored by means of temperature probes inserted into the subcutaneous and muscular tissues. If they are not affected, the hand and foot should be protected by an Esmarch band, a tourniquet should be placed proximally of the limb.

Once the limb is connected to the perfusion circuit, the infusion rate should be adjusted to 35-40 ml / unit limb volume (liter) / minute. The infusion line should be monitored with radioactive markers to detect any leakage from the limb to the systemic circulation (see Special warnings and precautions for use ). An adjustment of the infusion rate and tourniquet may be necessary to ensure a stabilization of the leakage rate in the systemic circulation to less than 10% (the level of systemic radioactivity must reach a plateau). The BEROMUN solution should be administered only if the systemic passage is less than 10%.

Once the temperature of the distal subcutaneous tissue has reached a temperature> 38 ° C (without exceeding 39 ° C), and when the pH of the perfusate is between 7.2 and 7.35, the BEROMUN solution must be bolus injected into the arterial part of the circuit. After 30 minutes of infusion of the BEROMUN solution alone, melphalan should be administered as a bolus into the reservoir of the circuit, or slowly into the arterial portion of the circuit. The temperature must then be increased to 39 ° C (without exceeding 40 ° C), at two different sites for measuring the temperature at the tumor. The duration of the infusion of the two associated products should be 60 minutes. The total duration of the infusion should be 90 minutes.

At the end of the infusion, the perfusate must be collected in the reservoir, while a rinsing liquid is added to the circuit maintaining the same flow rate of 35 to 40 ml / liter of volume of the limb per minute. This rinsing phase must be continued until a clear, rosy, transparent perfusate is obtained (see section Special warnings and precautions for use ).

Surgical resection of the residual tumor after ILP should be performed as soon as possible. If necessary, a second ILP may be performed 6 to 8 weeks after the first (see section 4.4 ).

Use in children

BEROMUN should not be used in children under the age of 18 due to the lack of data on safety and efficacy.

Against indications

The contraindications to the administration of BEROMUN by ILP classified according to the stages of the procedure, are:

Contraindications to the use of BEROMUN

Hypersensitivity to the active substance or to any of the excipients.

Serious cardiovascular diseases such as congestive heart failure (Class II, III or IV of the New York Heart Association classification), severe angina, arrhythmias, history of myocardial infarction in the previous 3 months, venous thrombosis, Peripheral peripheral arterial disease, recent history of pulmonary embolism.

Severe lung disease.

Evolutionary gastric ulcer or recent history of gastric ulcer.

Severe ascites.

Severe hematologic impairment, eg, number of leukocytes <2.5 x 10 9 / l, hemoglobin level <9 g / dl, platelet count <60 x 10 9 / l, hemorrhagic diathesis or ongoing bleeding disease.

Severe impairment of renal function, eg nephrotic syndrome, serum creatinine> 150 μmol / l or creatine clearance <50 ml / min.

Severe impairment of liver function, eg, aspartate-amino-transferase, alanine-amino-transferase or alkaline phosphatase greater than 2 times normal or bilirubin above 1.25 times normal.

Hypercalcemia> 12 mg / dl (2.99 mmol / l).

Patients in whom the use of vasopressors is contraindicated.

Patients in whom the use of anticoagulants is contraindicated.

Ongoing treatment with cardiotoxic substances (eg anthracyclines).

Pregnancy and lactation (see section on Pregnancy and lactation ).

Contraindications to the use of Melphalan

Refer to Melphalan's Summary of Product Characteristics.

Contraindications to the ILP technique

Severe ascites.

Severe lymphoedema of the limb.

Presence of contraindications to the use of vasopressors.

Patients in whom the use of anticoagulants is contraindicated.

Patients with a contraindication to the use of radioactive markers.

Presence of contraindications to hyperthermia of the limb.

Patients whose irrigation of the limb downstream of the tumor is thought to be very closely dependent on the tumor vessels. Arteriography may be necessary.

Pregnancy and breast feeding.

Beromun side effects

Adverse effects may be related to the administration of BEROMUN, melphalan, measures performed during the isolated limb perfusion technique, or a combination of these factors.

Adverse effects were ranked in order of frequency and regardless of severity, using the following convention:

Very common (≥1 / 10),

Frequent (≥1 / 100, <1/10),

Uncommon (≥1 / 1, 000, <1/100),

Rare (≥1 / 10, 000, <1/1000).

Systemic side effects:

In most patients, fever is usually mild to moderate.

Infections and infestations

Very common :

Infection,

Frequent

Septic syndrome.

Blood and lymphatic system disorders

Frequent

Thrombocytopenia, leukopenia.

Nervous system disorders

Frequent

Neurotoxicity, disorders of consciousness, headache.

Heart conditions

Very common :

Heart arrhythmias,

Frequent

Heart failure.

Respiratory, thoracic and mediastinal disorders

Frequent

respiratory distress syndrome.

Gastrointestinal disorders

Very common :

Nausea, vomiting,

Frequent

Constipation, diarrhea.

Hepatobiliary disorders

Very common :

Hepatic lesions.

Musculoskeletal and systemic disorders

Frequent

Myalgia.

Renal and urinary disorders

Frequent

proteinuria,

Rare :

Acute renal failure.

General disorders and administration site conditions

Very common :

Fever, asthenia, chills,

Frequent

Shock, hypotension, night sweats, hypersensitivity reactions.

Local side effects:

Nervous system disorders

Very common :

Pain in the treated limb, nerve damage.

Vascular disorders

Frequent

Arterial thrombosis, venous thrombosis.

Skin and subcutaneous tissue disorders

Very common :

Skin reaction, edema,

Frequent

Nail drop, cutaneous necrosis.

Musculoskeletal and systemic disorders

Frequent

Compartmental syndrome, muscle necrosis.

General disorders and administration site conditions

Very common :

Wound infection,

Frequent

Hypersensitivity reactions.

Serious adverse effects were observed among the effects listed above:

Serious systemic adverse reactions reported frequently (WHO grade III and IV, always below 10% but greater than 1%) were: liver injury, thrombocytopenia, fever, heart failure, leukopenia, shock, infection (including septic syndrome), respiratory distress syndrome and cardiac arrhythmia. Acute renal failure has been reported infrequently at a frequency of 0.4%.

Local serious adverse events such as muscle necrosis, cutaneous necrosis and compartment syndrome may be severe enough to require amputation.

Severe acute allergic reactions have been observed in patients treated with BEROMUN.

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