Posology : מינונים

4.2. Posology and method of administration
Melphalan is a cytotoxic drug which falls into the general class of alkylating agents. It should be prescribed only by physicians experienced in the management of malignant disease with such agents.
Since melphalan is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary (See section 4.4).
P osology
Parenteral administration:
For intravenous administration, it is recommended that MELPHALAN RAZ 50 MG solution is injected slowly into a fast-running infusion solution via a swabbed injection port.
If direct injection into a fast-running infusion is not appropriate, MELPHALAN RAZ 50 MG solution may be administered diluted in an infusion bag.
Melphalan is not compatible with infusion solutions containing dextrose, and it is recommended that ONLY Sodium Chloride intravenous infusion 0.9% w/v is used.
When further diluted in an infusion solution, MELPHALAN RAZ 50 MG has reduced stability and the rate of degradation increases rapidly with rise in temperature. If administration occurs at a room temperature of approximately 25°C, the total time from preparation of the injection solution to the completion of infusion should not exceed 1.5 hours.
Should any visible turbidity or crystallization appear in the reconstituted or diluted solutions, the preparation must be discarded.
Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see section 4.4).
If high-dose MELPHALAN RAZ 50 MG is administered with or without haematopoietic stem cell rescue, administration via a central venous line is recommended.


Populations

• Adults
MULTIPLE MYELOMA
MELPHALAN RAZ 50 MG has been used on an intermittent basis alone, at doses varying between 8mg/m 2 and 30 mg/m2 body surface area, given at intervals of between 2 to 6 weeks. Additionally, administration of prednisone has been included in a number of regimens. The literature should be consulted for precise details on treatment protocols.
A typical intravenous dosage schedule is 0.4 mg/kg bodyweight (16 mg/m 2 body surface area) repeated at appropriate intervals (e.g. once every 4 weeks), provided there has been recovery of the peripheral blood count during this period.
High-dose regimens generally employ single I.V. doses of between 100 and 200 mg/m 2 body surface area (approximately 2.5 to 5.0 mg/kg bodyweight), but haematopoietic stem cell rescue becomes essential following doses in excess of 140 mg/m 2 body surface area. In cases of renal impairment, the dose should be reduced by 50% (see Renal impairment). In view of the severe myelosuppression induced by high-dose MELPHALAN RAZ 50 MG, treatment should be confined to specialist centers with the appropriate facilities, and only be administered by experienced clinicians (see section 4.4).


OVARIAN ADENOCARClNOMA
When used intravenously as a single agent, a dose of 1 mg/kg body weight (approximately 40 mg/m 2 body surface area) given at intervals of 4 weeks has often been used.
When combined with other cytotoxic drugs, intravenous doses of between 0.3 and 0.4 mg/kg body weight (12 to 16 mg/m2 body surface area) have been used at intervals of 4 to 6 weeks.

• Children
Melphalan, within the conventional dosage range, is only rarely indicated in children and absolute dosage guidelines cannot be provided.

• Elderly
Although melphalan is frequently used at conventional dosage in the elderly, there is no specific information available relating to its administration to this patient sub-group.
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 RAZ 50 MG in elderly patients.
The pharmacokinetics of intravenous melphalan has not shown a correlation between age and melphalan clearance or with melphalan terminal elimination half-life. The limited data available do not support specific dosage adjustment recommendations for elderly patients receiving intravenous melphalan and suggested that current practice of dosage adjustment based upon the general condition of the geriatric patient and the degree of myelosuppression incurred during therapy should be continued.


• Renal impairment
Melphalan clearance, though variable, is decreased in renal impairment (see also Warnings and Precautions-Renal impairment).
When MELPHALAN RAZ 50 MG is used at conventional intravenous dosage (8 to 40 mg/m 2 body surface area), it is recommended that the initial dose should be reduced by 50% in patients with moderate to severe renal impairment and subsequent dosage determined according to the degree of haematological suppression.
For high intravenous doses of melphalan (100 to 240 mg/m 2 body surface area), the need for dose reduction depends upon the degree of renal impairment, whether haematopoietic stem cells are reinfused, and therapeutic need. As a guide for high dose melphalan treatment without haematopoietic stem cell rescue in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) a dose reduction of 50% is usual. High-dose melphalan without haematopoietic stem cell rescue is not recommended in patients with more severe renal impairment.

High dose melphalan with haematopoietic stem cell rescue has been used successfully even in dialysis dependent patients with end-stage renal failure. The relevant literature should be consulted for details.