Drug Class Description
Alkylating agent
Generic Name
Melphalan
Drug Description
Melphalan Hydrochloride BP equivalent to 50 mg mephalan per vial.
Presentation
Freeze-dried powder for injection.
Indications
Alkeran Injection, at conventional intravenous dosage, is indicated in the treatment of multiple myeloma and ovarian cancer. Alkeran Injection, at high intravenous dosage, is indicated, with or without haematopoietic stem cell transplantation, for the treatment of multiple myeloma and childhood neuroblastoma.Alkeran Injection, administered by regional arterial perfusion, is indicated in the treatment of localised malignant melanoma of the extremities and localised soft tissue sarcoma of the extremities. In the above indications, Alkeran may be used alone or in combination with other cytotoxic drugs.
Adult Dosage
Parenteral administration:Alkeran Injection is for intravenous use and regional arterial perfusion only. Alkeran Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.For intravenous administration, it is recommended that Alkeran 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, Alkeran Injection solution may be administered diluted in an infusion bag.Alkeran 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, Alkeran has reduced stability and the rate of degradation increases rapidly with rise in temperature. If Alkeran 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 Alkeran and in cases of poor peripheral venous access, consideration should be given to use of a central venous line.If high dose Alkeran 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: Alkeran 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 Alkeran 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 Alkeran 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 Alkeran 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.Dosage in renal impairmentAlkeran clearance, though variable, may be decreased in renal impairment.Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering Alkeran Tablets to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established.When Alkeran 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 Alkeran (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. Alkeran Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.As a guide, for high dose Alkeran 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 Alkeran (above 140 mg/m2) without haematopoietic stem cell rescue should not be used in patients with more severe renal impairment.High dose Alkeran 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.
Child Dosage
Alkeran, at conventional dosage, is only rarely indicated in children and dosage guidelines cannot be stated.High dose Alkeran 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.
Elderly Dosage
Although Alkeran 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 Alkeran in elderly patients is limited. Consideration should therefore be given to ensure adequate performance status and organ function, before using high dose Alkeran Injection in elderly patients.
Contra Indications
Alkeran should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan.
Special Precautions
Alkeran 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. As with all high dose chemotherapy, precautions should be taken to prevent tumour lysis syndrome.Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.Since Alkeran is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary.Alkeran Injection solution can cause local tissue damage, should extravasation occur and consequently, it should not be administered by direct injection into a peripheral vein. It is recommended that Alkeran Injection solution is administered by injecting slowly into a fast-running intravenous infusion via a swabbed injection port, or via a central venous line.In view of the hazards involved and the level of supportive care required, the administration of high dose Alkeran Injection should be confined to specialist centres, with the appropriate facilities and only be conducted by experienced clinicians.In patients receiving high dose Alkeran Injection, consideration should be given to the prophylactic administration of anti-infective agents and the administration of blood products as required.Consideration should be given to ensure adequate performance status and organ function before using high dose Alkeran Injection. Alkeran Injection should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practised when either partner is receiving Alkeran.Safe handling of AlkeranThe handling of Alkeran 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 Alkeran 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. Alkeran should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.Renal ImpairmentAlkeran 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 FertilityAlkeran 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 Alkeran can have an adverse effect on spermatogenesis. Therefore, it is possible that Alkeran 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
Interactions
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic entercolitis.Impaired renal function has been described in bone marrow transplant patients who received high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.
Adverse Reactions
For this product there is no modern clinical documentation which can be used as support for determining the frequency of undesirable effects. Undesirable effects may vary in their incidence depending on the indication and dose received and also when given in combination with other therapeutic agents.The following convention has been utilised for the classification of frequency:- Very common 1/10, common 1/100, <1/10, uncommon 1/1000 and <1/100, rare 1/10,000 and <1/1000, very rare <1/10,000.Blood and Lymphatic System DisordersVery common: bone marrow depression leading to leucopenia, thrombocytopenia and anaemiaRare: haemolytic anaemiaImmune System DisordersRare: allergic reactions (see Skin and Subcutaneous Tissue Disorders)Allergic reactions to melphalan such as urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after intravenous administration. Cardiac arrest has also been reported rarely in association with such events.Respiratory, Thoracic and Mediastinal DisordersRare: interstitial pneumonitis and pulmonary fibrosis (including fatal reports)Gastrointestinal DisordersVery common: nausea, vomiting and diarrhoea; stomatitis at high doseRare: stomatitis at conventional doseThe incidence of diarrhoea, vomiting and stomatitis becomes the dose-limiting toxicity in patients given high intravenous doses of melphalan in association with autologous bone marrow transplantation. Cyclophosphamide pretreatment appears to reduce the severity of gastro-intestinal damage induced by high-dose melphalan and the literature should be consulted for details.Hepatbiliary DisordersRare: hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice; venoocclusive disease following high dose treatmentSkin and Subcutaneous Tissue DisordersVery common: alopecia at high doseCommon: alopecia at conventional doseRare: maculopapular rashes and pruritus (see Immune System Disorders)Musculoskeletal and Connective Tissue DisordersInjection, following isolated limb perfusion:Very common: muscle atrophy, muscle fibrosis, myalgia, blood creatine phosphokinase increased.Common: compartment syndromeNot known: muscle necrosis, rhabdomyolysisRenal and Urinary DisordersCommon: temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damageGeneral Disorders and Administration Site ConditionsVery common: subjective and transient sensation of warmth and/or tingling
Manufacturer
GlaxoSmithKline
Drug Availability
(POM)
Updated
11 August 2009
