Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132 JH Hoofddorp, The Netherlands
Melphalan, at conventional intravenous dosage, is indicated in the treatment of multiple myeloma and advanced ovarian cancer.
Melphalan, at high intravenous dosage, is indicated, with or without haematopoietic stem cell transplantation, for the treatment of multiple myeloma and childhood neuroblastoma.
Melphalan, administered by regional arterial perfusion, is indicated in the treatment of localized malignant melanoma of the extremities and localized soft tissue sarcoma of the extremities.
In the above indications, melphalan may be used alone or in combination with other cytotoxic drugs.
Treatment with melphalan should be supervised by a physician experienced in the use of anticancer therapies.
Melphalan is for intravenous use and regional arterial perfusion only. Melphalan should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m².
For intravenous administration, it is recommended that melphalan 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 may be administered diluted in an infusion bag.
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 is administered with or without autologous bone marrow transplantation, administration via a central venous line is recommended. In view of the hazards involved and the level of supportive care required (see section 4.4), the administration of high dose melphalan should be confined to specialist centres, with the appropriate facilities and only be conducted by experienced clinicians.
For regional arterial perfusion, the literature should be consulted for detailed methodology.
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 sections 4.4 and 4.8).
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.
Protect the patient during intravenous administration against external contact with the melphalan solution for injection/infusion (see section 4.4).
Melphalan 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
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.
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.
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.
Hyperthermic regional perfusion with melphalan has been used as an adjuvant to surgery for early malignant melanoma and as palliative treatment for advanced but localized disease. The scientific literature should be consulted for details of perfusion technique and dosage used.
Hyperthermic regional perfusion with melphalan has been used in the management of all stages of localized soft tissue sarcoma, usually in combination with surgery.
Melphalan, at conventional dosage, is only rarely indicated in children and dosage guidelines cannot be stated.
High dose melphalan, in association with haematopoietic stem cell rescue, has been used in childhood neuroblastoma and dosage guidelines based on body surface area may be used.
Although 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 in elderly patients.
Melphalan 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 to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established. When melphalan is used at conventional intravenous dosage (8-40 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. 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 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.
For instructions on reconstitution, and if applicable dilution, of the medicinal product before administration, see section 6.6.
After reconstitution the appearance of the medicinal product should be a clear solution, see section 6.6.
Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. The immediate effects of acute intravenous overdosage are nausea and vomiting. Damage to the gastro-intestinal mucosa may also ensue and diarrhoea, sometimes haemorrhagic, has been reported after overdosage. The principal toxic effect is bone marrow suppression, leading to leucopenia, thrombocytopenia and anaemia.
General supportive measures, together with appropriate blood and platelet transfusions, should be instituted if necessary and consideration given to hospitalization, antibiotic cover, the use of haematological growth factors.
There is no specific antidote. The blood picture should be closely monitored for at least four weeks following overdosage until there is evidence of recovery.
Shelf life: 2 years.
Chemical and physical in use stability have been demonstrated for 1 hour at room temperature.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are responsibility of user. Any unused portion should be discarded.
Do not store above 30°C. Do not refrigerate.
Keep the vial in the outer carton in order to protect from light.
Powder: Clear, glass vial with a bromobutyl rubber stopper and aluminium collar with a plastic flip-top cover.
Pack size: one vial containing 50 mg melphalan.
Solvent: Clear, glass vial with a bromobutyl rubber stopper and aluminium collar with a plastic flip-top cover.
Pack size: one vial containing 10 ml of solvent.
Safe Handling of Melphalan:
Melphalan should be prepared for administration by a trained professional who is familiar with its properties and safe handling requirements. Refer to local cytotoxic guidelines before commencing. For instructions on administration, see Section 4.2.
Melphalan should be prepared for use in the aseptic unit of a pharmacy equipped with a suitable vertical laminar flow cabinet. Where such a facility is not available, a specially designated side room of a ward or clinic may be used.
Personnel preparing or handling Melphalan should wear the following protective clothing:
Disposable gloves of surgical latex or polyvinylchloride of a suitable quality (rubber gloves are not adequate);
Surgical facemask of suitable quality;
Protective goggles or glasses which should be washed thoroughly with water after use;
Disposable apron.
In an aseptic facility, other suitable clothing will be required.
Any spillage should be dealt with immediately (by personnel wearing suitable protective clothing), by mopping with damp, disposable paper towels which are placed in a high-risk waste disposal bag after use and disposed of in compliance with relevant local legislation. Contaminated surfaces should be washed with copious quantities of water.
Should Melphalan solution come into contact with the skin, wash immediately and thoroughly with soap and plenty of cold water. In such instances it may be prudent to seek medical advice.
In case of contact with eyes, IMMEDIATE irrigation with sodium chloride eye wash should be carried out and medical attention sought without delay. If sodium chloride solution is not available, large volumes of water may be used.
Staff who are pregnant or trying to conceive should not handle Melphalan.
Melphalan should be prepared at 25°C, by reconstituting the freeze-dried powder/cake with the solvent-diluent provided.
It is important that both the freeze-dried powder/cake 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.
| Vial size | Volume of diluent to be added to vial | Approximate available volume | Nominal concentration per ml |
|---|---|---|---|
| 50 mg | 10 ml | 10 ml | 5 mg/ml |
Melphalan solution has limited stability and should be prepared immediately before use.
The reconstituted solution should not be refrigerated as this will cause precipitation.
Immediately withdraw reconstituted solution having concentration of 5 mg/ml of anhydrous melphalan from reconstituted vial and add using 10 ml new syringe into infusion bag containing of 0.9% Sodium Chloride Intravenous Infusion. Mix this diluted solution thoroughly by manual rotation to give nominal concentration of 0.45 mg/ml of anhydrous melphalan.
| Reconstituted volume to be added in infusion bag | Volume of 0.9% sodium chloride intravenous infusion | Approximate available volume | Nominal concentration per ml |
|---|---|---|---|
| 10 ml (50mg) | 100 ml | 110 ml | 0.45 mg/ml |
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 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.
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.
Should any visible turbidity or crystallisation appear in the reconstituted or diluted solutions the preparation must be discarded.
Any solution unused after one hour should be discarded according to standard guidelines for handling and disposal of cytotoxic drugs.
Disposal of sharp objects, such as needles, syringes, administration sets and ampoules should be in rigid containers labelled with a suitable hazard warning seal. Personnel involved in disposal should be aware of the precautions to be observed, and the material should be destroyed by incineration if appropriate.
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