ALKERAN FOR INJECTION 50 mg/vial

INJECTION

**Dosage and Administration** **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 Warnings and Precautions – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Thromboembolic events** Melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone is associated with 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 section 4.4 and section 4.8_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). 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** _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 prednisone 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 bodyweight (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 bodyweight), 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). 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 be experienced clinicians (see Warnings and Precautions – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). **Advanced ovarian adenocarcinoma** When used intravenously as a single agent, a dose of 1 mg/kg bodyweight (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 bodyweight (12 to 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 Safe Handling of _ALKERAN_ in _Instructions for Use/Handling_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). _ALKERAN_ Injection should be prepared, AT ROOM TEMPERATURE, by reconstituting the freeze-dried powder with the Solvent-Diluent provided. If the Solvent-Diluent is used at cold temperature, _ALKERAN_ FD powder may not reconstitute properly and undissolved particles may be observed. 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 at least 50 seconds) until a clear solution, without visible particles, is obtained. Each vial must be reconstituted individually in this manner. Slow diluents addition and delaying the shaking may lead to the formation of insoluble particles. It should be noticed that the shaking process creates a considerable amount of very small air bubbles. These bubbles may persist and may take further 2 or 3 minutes to clear, as the resulting solution is quite viscous. This could make difficult the evaluation on solution clearness. The resulting solution contains the equivalent of 5 mg per ml anhydrous melphalan and has a pH of approximately 6.5. _ALKERAN_ Injection solution has limited stability and should be prepared immediately before use. Any unused solution should be discarded ( _See Pharmaceutical Information–Use and Handling_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). The reconstituted solution should not be refrigerated as this will cause precipitation. **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. When further diluted in an infusion solution, _ALKERAN_ Injection 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 _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** 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 Dosage in children, Advanced neuroblastoma in childhood). _ALKERAN_, within the conventional dosage range, is only rarely indicated in children and absolute dosage guidelines cannot be provided. **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. 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 of the geriatric patient and the degree of myelosuppression incurred during therapy should be continued. **Dosage in renal impairment** ( _See Warnings and Precautions_ – _please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information_). _ALKERAN_ clearance, though variable, may be decreased in renal impairment. 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.