Summary of Product Characteristics Updated 09-Dec-2014 | Aspen
Parenteral administration:Melphalan Injection is for intravenous use and regional arterial perfusion only. Melphalan Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.For intravenous administration, it is recommended that Melphalan Injection 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 Injection 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 has reduced stability and the rate of degradation increases rapidly with rise in temperature. If Melphalan is infused 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 crystallisation 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.If high dose Melphalan Injection is administered with or without autologous bone marrow transplantation, administration via a central venous line is recommended.For regional arterial perfusion, the literature should be consulted for detailed methodology.Multiple myeloma: Melphalan Injection is administered on an intermittent basis alone, or in combination with other cytotoxic drugs. Administration of prednisone has also been included in a number of regimens. When used as a single agent, a typical intravenous Melphalan dosage schedule is 0.4 mg/kg body weight (16 mg/m2 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 intravenous doses of between 100 and 200 mg/m2 body surface area (approximately 2.5 to 5.0 mg/kg body weight), but haematopoietic stem cell rescue becomes essential following doses in excess of 140 mg/m2 body surface area. Hydration and forced diuresis are also recommended. Ovarian adenocarcinoma: When used intravenously as a single agent, a dose of 1 mg/kg body weight (approximately 40 mg/m2 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.Advanced neuroblastoma: Doses of between 100 and 240 mg/m2 body surface area (sometimes divided equally over 3 consecutive days) together with haematopoietic stem cell rescue, have been used either alone or in combination with radiotherapy and/or other cytotoxic drugs.Malignant melanoma: Hyperthermic regional perfusion with Melphalan has been used as an adjuvant to surgery for early malignant melanoma and as palliative treatment for advanced but localised disease. The scientific literature should be consulted for details of perfusion technique and dosage used. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg bodyweight and for lower extremity perfusions is 0.8-1.5 mg/kg body weight.Soft tissue sarcoma: Hyperthermic regional perfusion with Melphalan has been used in the management of all stages of localised soft tissue sarcoma, usually in combination with surgery. A typical dose range for upper extremity perfusions is 0.6-1.0 mg/kg body weight and for lower extremity perfusions is 1-1.4 mg/kg body weight.
Use in ChildrenMelphalan, at conventional dosage, is only rarely indicated in children and dosage guidelines cannot be stated.High dose Melphalan Injection, in association with haematopoietic stem cell rescue, has been used in childhood neuroblastoma and dosage guidelines based on body surface area, as for adults, may be used.
Use in the elderlyAlthough 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 Injection in elderly patients.
Dosage in renal impairmentMelphalan clearance, though variable, may be decreased in renal impairment. Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering Melphalan Tablets to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established. When Melphalan Injection is used at conventional intravenous dosage (16-40 mg/m2 body surface area), it is recommended that the initial dose should be reduced by 50% and subsequent dosage determined according to the degree of haematological suppression.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 therapeutic need. Melphalan Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.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 (above 140 mg/m2) without haematopoietic stem cell rescue should not be used 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.
Safe handling of MelphalanThe handling of Melphalan formulations should follow guidelines for the handling of cytotoxic drugs according to the Royal Pharmaceutical Society of Great Britain Working Party on the handling of cytotoxic drugs.
MonitoringSince Melphalan is a potent myelosuppressive agent, it is essential that careful attention should be paid to the monitoring of blood counts, to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia. Blood counts may continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in leukocyte or platelet counts, treatment should be temporarily interrupted. Melphalan should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.
Renal ImpairmentMelphalan clearance may be reduced in patients with renal impairment who may also have uraemic marrow suppression. Dose reduction may therefore be necessary (see Posology and Method of Administration). See Undesirable Effects for elevation of blood urea.
MutagenicityMelphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
CarcinogenicityMelphalan, in common with other alkylating agents, has been reported to be leukaemogenic. There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.A comparison of patients with ovarian cancer who received alkylating agents with those who did not, showed that the use of alkylating agents, including melphalan, significantly increased the incidence of acute leukaemia.The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.
Effects on FertilityMelphalan causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.There is evidence from some animal studies that Melphalan can have an adverse effect on spermatogenesis. Therefore, it is possible that Melphalan may cause temporary or permanent sterility in male patients.The label for the product will contain the following statements:Keep out of the reach of children.Store below 30° CDo not refrigerate.Protect from light
|Blood and Lymphatic System Disorders|
|Very common:||bone marrow depression leading to leucopenia, thrombocytopenia and anaemia|
|Immune System Disorders|
|Rare:||allergic reactions (see Skin and Subcutaneous Tissue Disorders)|
|Respiratory, Thoracic and Mediastinal Disorders|
|Rare:||interstitial pneumonitis and pulmonary fibrosis (including fatal reports)|
|Very common:||nausea, vomiting and diarrhoea; stomatitis at high dose|
|Rare:||stomatitis at conventional dose|
|Rare:||hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice; veno-occlusive disease following high dose treatment|
|Skin and Subcutaneous Tissue Disorders|
|Very common:||alopecia at high dose|
|Common:||alopecia at conventional dose|
|Rare:||maculopapular rashes and pruritus (see Immune System Disorders)|
|Musculoskeletal and Connective Tissue Disorders|
|Injection, following isolated limb perfusion:|
|Very common:||muscle atrophy, muscle fibrosis, myalgia, blood creatine phosphokinase increased.|
|Not known:||muscle necrosis, rhabdomyolysis|
|Renal and Urinary Disorders|
|Common:||temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage|
|General Disorders and Administration Site Conditions|
|Very common:||subjective and transient sensation of warmth and/or tingling|
Preparation of Melphalan Injection Solution:Melphalan Injection should be prepared at room temperature (approximately 25°C), by reconstituting the freeze-dried powder with the solvent-diluent provided. It is important that both the freeze-dried powder and the solvent provided are at room temperature before starting reconstitution. Warming the diluent in the hand may aid reconstitution. 10 ml of this vehicle should be added quickly, as a single quantity into the vial containing the freeze dried powder, and immediately shaken vigorously (for approximately 1 minute) until a clear solution, without visible particles, is obtained. Each vial must be reconstituted individually in this manner. The resulting solution contains the equivalent of 5 mg per ml anhydrous melphalan and has a pH of approximately 6.5. Melphalan Injection solution has limited stability and should be prepared immediately before use. Any solution unused after one hour should be discarded according to standard guidelines for handling and disposal of cytotoxic drugs.The reconstituted solution should not be refrigerated as this will cause precipitation.