ALKERAN FOR INJECTION 50 MG/VIAL [SIN11873P]

Product Info

ALKERAN FOR INJECTION 50 MG/VIAL

[SIN11873P]

Indications

ALKERAN Injection, administered by regional arterial perfusion, is indicated in the treatment of:

localised malignant melanoma of the extremities;

localised soft tissue sarcoma of the extremities.

ALKERAN Injection, at conventional intravenous dosage, may be used in the treatment of:

multiple myeloma: ALKERAN Injection, either alone or in combination with other cytotoxic drugs, is as effective as the oral formulation in the treatment of multiple myeloma;

advanced ovarian cancer: ALKERAN injection produces an objective response in approximately 50% of the patients with advanced ovarian adenocarcinoma, when given alone, or in combination with other cytotoxic drugs.

ALKERAN Injection, at high intravenous dosage, may be used in the treatment of:

multiple myeloma: complete remissions have been achieved in up to 50% of patients given high-dose ALKERAN Injection, with or without haematopoietic stem cell rescue, either as first-line treatment or to consolidate a response to conventional cytoreductive chemotherapy.

advanced neuroblastoma in childhood: high-dose ALKERAN Injection with haematopoietic stem cell rescue has been used either alone, or combined with radiotherapy and/or other cytotoxic drugs, to consolidate a response to conventional treatment.

A significant increase in the duration of disease-free survival was demonstrated in a prospective randomised trial of high-dose ALKERAN injection versus no further treatment.

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.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section SCOPE – Excipients – please refer to the Product Insert/Patient Information Leaflet published on HSA for the full drug information.

• Lactation