Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: ADIENNE S.r.l. S.U., Via Galileo Galilei, 19, 20867 Caponago (MB), Italy, tel: +39 0240700445, e-mail: adienne@adienne.com
High-dose of PHELINUN used alone or in combination with other cytotoxic medicinal products and/or total body irradiation is indicated in the treatment of:
PHELINUN in combination with other cytotoxic medicinal products is indicated as reduced intensity conditioning (RIC) treatment prior to allogeneic haematopoietic stem cell transplantation (allo-HSCT) in malignant haematological diseases in adults.
PHELINUN in combination with other cytotoxic medicinal products is indicated as conditioning regimen prior to allogeneic haematopoietic stem cell transplantation in haematological diseases in the paediatric population as:
PHELINUN administration must be supervised by a physician experienced in the use of chemotherapeutic medicinal products and in conditioning treatment prior to haematopoietic stem cell transplantation.
Thrombosis prophylaxis needs to be administered during at least the first 5 months of the treatment, in particular to patients who are more at risk of thrombosis. The decision to take antithrombotic prophylactic measures needs to be taken after a thorough assessment of the underlying risks for the individual patient (see sections 4.4 and 4.8).
Should thromboembolic complications occur for the patient, treatment needs to be stopped and the standard anticoagulant therapy needs to be started. As soon as the patient is stabilised by the anticoagulant therapy and the complications of the thromboembolic incident are under control, melphalan can be used in combination with lenalidomide and prednisone, or thalidomide and prednisone or dexamethasone can be resumed in the original dose contingent on the assessment of the risks and benefits. The patient needs to continue the anticoagulant therapy during the melphalan treatment.
The dose regimen is as follows: one dose between 100 and 200 mg/m² body surface area (approximatively 2.5 to 5.0 mg/kg body weight). The dose can be divided equally over 2 or 3 consecutive days. Autologous hematopoietic stem cell transplantation is required following doses above 140 mg/m² body surface area.
The recommended dose is 140 mg/m² as a single daily infusion or 70 mg/m² once daily for two consecutive days.
The dose regimen is as follows: one dose between 100 and 200 mg/m² body surface area (approximatively 2.5 to 5.0 mg/kg body weight). The dose can be divided equally over 2 or 3 consecutive days. Autologous hematopoietic stem cell transplantation is required following doses above of 140 mg/m² body surface area.
The recommended dose to consolidate a response obtained with a conventional treatment is one single dose between 100 mg/m² and 240 mg/m² body surface area (sometimes divided equally over 3 consecutive days) together with autologous haematopoietic stem cell transplantation. The infusion is used either alone or in combination with radiotherapy and/or other cytotoxic medicinal products.
The recommended dose is as follows:
There is no dose recommendation for the administration of PHELINUN to elderly. However, frequently conventional doses of melphalan are applied in the elderly. Experience in the use of high dose melphalan in elderly patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function, before using high dose melphalan in elderly patients.
The posology should be adjusted in patients with renal impairment (see section 4.4). The clearance of melphalan, although variable, may be reduced with impaired renal function. High-dose melphalan with haematopoietic stem cell rescue has been used successfully even in dialysis dependent patients with end-stage renal failure.
For high intravenous doses of melphalan (100 to 240 mg/m² body surface area), the need for dose reduction depends upon the degree of renal impairment, whether haematopoietic stem cells are re-infused, and the therapeutic need. Melphalan injection should not be given without haematopoietic stem cell rescue at doses above 140 mg/m².
PHELINUN is for intravenous use only.
Risk of extravasation could be observed when PHELINUN is administered via peripheral intravenous route. In case of extravasation, the administration should be interrupted immediately and a central venous line route should be used.
If high-dose PHELINUN is administered with or without transplantation, the administration as dilution via a central venous line is recommended to avoid extravasation. It is recommended that PHELINUN as concentrate (5 mg/ml) is injected slowly into the port of a fastrunning infusion solution.
If the injection of the concentrate (5 mg/ml) slowly into a fast-running infusion solution is not appropriate, PHELINUN may be administered further diluted with sodium chloride 9 mg/ml (0.9%) solution for injection in a “slow-running” solution in a infusion bag. The total time from preparation of the solution to the completion of infusion should not exceed 1 hour and 30 minutes. When further diluted in an infusion solution, PHELINUN has reduced stability and the rate of degradation increases rapidly with rise in temperature.
It is recommended to let the infusion run at a temperature below 25°C.
The preparation of injectable cytotoxic solutions must be carried out by qualified healthcare professionals with knowledge of alkylating agents handling, under conditions that ensure the environment protection and the healthcare professional safety. PHELINUN should be prepared for use in a dedicated preparation area. Healthcare professionals must have a suitable equipment, including long-sleeved clothes, face protection, protective caps, safety goggles, sterile disposable gloves, worktop protection shields, containers and bags for collecting waste. Any broken container should be treated with the same precautions and considered as contaminated waste. Excreta and vomit must be handled with care. Pregnantstaffshould be warned and avoid handling PHELINUN.
If PHELINUN accidentally contacts the skin, this must be immediately washed thoroughly with soap and water.
In case of accidental contact with the eyes or mucous membranes, rinse abundantly with water.
Inhalation of the product should be avoided.
Remnants of the medicinal product as well as all materials that have been used for reconstitution and administration must be disposed of according to standard procedures applicable to cytotoxic products, with due regard to local requirements related to the disposal of hazardous waste.
For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6.
Gastro-intestinal effects, including nausea and vomiting are the most likely signs of acute intravenous overdose. Damage to the gastro-intestinal mucosa may also occur. Diarrhoea, sometimes haemorrhagic, has been reported after intravenous overdose. The principal toxic effect is bone marrow suppression, leading to anaemia, neutropenia and thrombocytopenia.
There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdose until there is evidence of recovery. The treatment should be symptomatic: blood transfusion, antibiotic therapy, haematopoietic growth factors if necessary.
PHELINUN 50 mg powder and solvent for concentrate for solution for infusion:
Unopened vial: 3 years.
PHELINUN 200 mg powder and solvent for concentrate for solution for infusion:
Unopened vial: 30 months.
After reconstitution and dilution:
After reconstitution and dilution, chemical and physical stability has been demonstrated for 1 hour and 30 minutes at 25°C. Therefore the total time from reconstitution and dilution to the completion of infusion should not exceed 1 hour and 30 minutes. From a microbiological point of view, the product should be used immediately after reconstitution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.
The reconstituted solution should not be refrigerated as this will cause precipitation.
Do not refrigerate.
Keep the vials in the outer carton in order to protect from light.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
Powder: Type I glass vial closed with coated chlorobutyl rubber stopper and sealed with aluminium flip-off cap.
Solvent: Type I glass vial closed with coated chlorobutyl rubber stopper and sealed with aluminium flip-off cap.
Pack size: one vial containing 50 mg or 200 mg melphalan and one vial containing 10 ml or 40 ml of solvent.
The powder should be reconstituted immediately after opening the vial.
PHELINUN should be prepared at a temperature below 25°C, by reconstituting the freeze-dried powder with 10 ml or 40 ml solvent and immediately shaking vigorously until a clear solution, without visible particles, is obtained. Only clear solution free from particles should be used.
Unless the concentrate is administered into a fast-running infusion solution via injection port, the reconstituted solution must be further diluted prior to administration with an appropriate volume of sodium chloride 9 mg/ml (0.9%) solution for injection in order to obtain a final concentration between 0.45 and 4.0 mg/ml.
PHELINUN concentrate and solution have limited stability and should be prepared immediately before use.
The maximum time between reconstitution and dilution of the solution in sodium chloride 9 mg/ml (0.9%) solution for injection and the end of the infusion is 1 hour 30 minutes.
The procedures for the safe handling and disposal of antineoplastic agents must be followed by healthcare professionals or medical personnel and should comply with the current recommendations for cytotoxic medicinal products (see section 4.2).
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
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