General: 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.
Since ALKERAN is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary (see Precautions).
The absorption of melphalan after oral administration is variable.
Dosage may need to be cautiously increased until myelosuppression is seen, in order to ensure that potentially therapeutic levels have been reached.
Tab: Thromboembolic events: Melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone is associated with an increased risk of venous thromboembolism. Thromboprophylaxis should be administered for at least the first 5 months of treatment especially in patients with additional thrombotic risk factors. The decision to take antithrombotic prophylactic measures should be made after careful assessment of an individual patient's underlying risk factors (see Precautions and Adverse Reactions).
If the patient experiences any thromboembolic events, treatment must be discontinued and standard anticoagulation therapy started. Once the patient has been stabilised on the anticoagulation treatment and any complications of the thromboembolic event have been managed, melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone may be restarted at the original dose dependent upon a benefit-risk assessment. The patient should continue anticoagulation therapy during the course of melphalan treatment.
Multiple Myeloma: A typical oral dosage schedule is 0.15 mg/kg body weight daily in divided doses for 4 days repeated at intervals of 6 weeks. Numerous regimens have, however, been used and the scientific literature should be consulted for details.
The administration of oral melphalan and prednisone may be more effective than melphalan alone. The combination is usually given on an intermittent basis.
Prolonging treatment beyond one year in responders does not appear to improve results.
Advanced Ovarian Adenocarcinoma: A typical regimen is 0.2 mg/kg body weight daily orally for 5 days. This is repeated every 4-8 weeks or as soon as the peripheral blood count has recovered.
Carcinoma of the breast: Melphalan has been given orally at a dose of 0.15 mg/kg body weight or 6 mg/m2 body surface area/day for 5 days and repeated every 6 weeks. The dose was decreased if bone marrow toxicity was observed.
Polycythaemia rubra vera: For remission induction, doses of 6 to 10 mg daily for 5 to 7 days have been used, after which 2 to 4 mg daily were given until satisfactory disease control was achieved.
A dose of 2 to 6 mg once per week has been used for maintenance therapy.
In view of the possibility of severe myelosuppression if melphalan is given on a continuous basis, it is essential that frequent blood counts are taken throughout therapy, with dosage adjustment or breaks in treatment, as appropriate, to maintain careful haematological control.
Inj: Multiple myeloma: ALKERAN injection has been used on an intermittent basis alone, or in combination with other cytotoxic drugs, at doses varying between 8 mg/m2 body surface area and 30 mg/m2 body surface area, given at intervals of between 2 to 6 weeks. Additionally, administration of prednisolone has been included in a number of regimens. The literature should be consulted for precise details on treatment protocols.
When used as a single agent, a typical intravenous 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 mg/kg body weight), but haematopoietic stem cell rescue becomes essential following doses in excess of 140 mg/m2 body surface area. In cases of renal impairment, the dose should be reduced by 50% (see Dosage in renal impairment as follows). In view of the severe myelosuppression induced by high-dose ALKERAN injection, treatment should be confined to specialist centres with the appropriate facilities, and only be administered by experienced clinicians (see Precautions).
Advanced 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 (12-16 mg/m2 body surface area) have been used at intervals of 4 to 6 weeks.
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.
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.
ALKERAN has also been given with actinomycin D and the scientific literature should be consulted for details of dosage regimens.
Advanced neuroblastoma in childhood: Doses including 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.
Preparation of ALKERAN Injection Solution: (see Instructions for Use/Handling under Cautions for Usage).
Parenteral administration: Except in cases where regional arterial perfusion is indicated, ALKERAN Injection is for intravenous use only.
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 Injection is not compatible with infusion solutions containing dextrose, and it is recommended that ONLY Sodium Chloride Intravenous Infusion 0.9% w/v is used.
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.
Use in children: ALKERAN, within the conventional dosage range, is only rarely indicated in children and absolute dosage guidelines cannot be provided.
Inj: High-dose ALKERAN Injection, in association with bone marrow rescue, has been used in childhood neuroblastoma and dosage guidelines based on body surface area are used in this situation (see Advanced neuroblastoma in childhood as previously mentioned).
Use in the elderly: 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.
Inj: Experience in the use of 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.
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 if the geriatric patient and the degree of myelosuppression incurred during therapy should be continued.
Dosage in renal impairment: ALKERAN clearance, though variable, may be decreased in renal impairment (see Precautions).
Tab: Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering melphalan to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established.
Inj: When ALKERAN Injection is used at conventional intravenous dosage (8 to 40 mg/m2 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 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 reinfused and therapeutic need.
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 without haematopoietic stem cell rescue is not recommended 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.