MELPHALAN

Melphalan should only be prescribed for patients by a specialist doctor who is experienced in management of malignant disease. As melphalan is a myelosuppressive agent, it is necessary to perform blood count test during therapy. If necessary, discontinue administration or adjust dose.

The use of Melphalan should only be performed with careful haematological control. 4).

Posology Parenteral administration:

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.

Multiple myeloma:

Melphalan is administered on an intermittent basis alone, or in combination with other cytotoxic medicinal products. Administration of prednisone has also been included in a number of regimens. g. once every 4 weeks), provided there has been recovery of the peripheral blood count during this period.

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. 4 mg/kg body weight (12 to 16 mg/m2body 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 medicinal products.

Malignant melanoma:

Hyperthermic regional perfusion with melphalan 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.

5 mg/kg body weight.

Soft tissue sarcoma:

Hyperthermic regional perfusion with melphalan has been used in the management of all stages of localised soft tissue sarcoma, usually in combination with surgery. 4 mg/kg body weight. Paediatric population Melphalan, at conventional dosage, is only rarely indicated in the paediatric population 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, as for adults, may be used. Elderly 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. The pharmacokinetics of intravenous melphalan did not show a correlation between age and melphalan clearance or terminal elimination half-life of melphalan.

The limited data available does not support specific recommendations for dose adjustment in elderly patients receiving melphalan intravenously. It is recommended that the current practice of dose adjustment be continued based on the general condition of the elderly and the degree of myelosuppression during therapy.

Renal impairment Melphalan clearance, though variable, may be decreased in renal impairment. When Melphalan 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 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. Melphalan should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2.

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 (above 140 mg/m2) without haematopoietic stem cell rescue should not be used in patients with more severe renal impairment.

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. Thromboembolic events Patients undergoing melphalan therapy in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone should receive a thrombosis prophylaxis at least during the first 5 months of treatment due to an increased risk of venous thromboembolism (predominantly deep vein thrombosis and pulmonary embolism), especially if there are other thrombogenic risk factors.

8) for each patient. If a thromboembolic event […]

For this medicinal 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.

Adverse reactions are listed below by system organ class and frequency grouping. The frequencies are defined as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare ≥ 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

MedDRA system organ class Frequency Adverse events Neoplasms benign, malignant and unspecified (incl. 4) Very common Bone marrow depression, which manifests as leukocytopenia, thrombocytopenia and anaemia. Blood and lymphatic system disorders Rare Hemolytic Anaemia1 Immune system disorders Rare Allergic reactions (see also skin and subcutaneous tissue disorders)2.

Respiratory, thoracic and mediastinal disorders Rare Interstitial pneumonitis and pulmonary fibrosis (including fatal cases). Very commo n nausea, diarrhoea and vomiting, stomatitis at high doses. Gastrointestinal disorders Rare Stomatitis with conventional dose.

Hepatobiliary disorders Rare Hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice; veno-occlusive disease after high-dose therapy. Very commo n Alopecia at high dose.

Common Alopecia at conventional dose Skin and subcutaneous tissue disorders Rare Maculopapular exanthemia and pruritus (see also immune system disorders). Very commo n Muscular atrophy, muscle fibrosis, myalgia, increase in creatine phosphokinase in the blood.

Common Compartment Syndrome Musculoskeletal and connective tissue disorders (after parenteral administration for regional perfusion of the extremities) Not known Muscle necrosis, rhabdomyolysis. 4) Vascular disorders Not known Deep vein thrombosis, pulmonary embolism General disorders and administration site conditions Very commo n Subjective and transient heat sensation and/or tingling 1 Since melphalan is a strongly myelosuppressive agent, careful monitoring of the blood values is imperative to avoid excessive bone marrow depression and the risk of irreversible bone marrow aplasia.

Since the blood values can continue to drop even after termination of the therapy, the treatment should be interrupted at the first sign of an unusually severe drop in leukocyte or platelet values. 2 Allergic reactions such as urticaria, edema, rashes, and anaphylactic shock occur in the initial and follow-up treatment, especially in the case of intravenous melphalan treatment.

Cardiac arrest has been reported in rare cases in connection with the allergic reactions. 3 Temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Melphalan 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. Melphalan 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 Melphalan 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 Melphalan should be confined to specialist centres, with the appropriate facilities and only be conducted by experienced clinicians.

In patients receiving high dose Melphalan, 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 Melphalan.

Melphalan injections should not be given without haematopoietic stem cell rescue at doses of above 140 mg/m2. As with any cytotoxic chemotherapy, adequate contraceptive precautions should be practiced when either partner is receiving Melphalan up to six months after end of treatment.

For ovarian cancer, non-hormonal contraceptive methods are advised. Safe handling of Melphalan The handling of melphalan formulations should follow guidelines for the handling of cytotoxic drugs. The eyes, skin and the mucous membranes of patients need to be protected against contact with the melphalan solution for injection/infusion or reconstituted solution.

Monitoring Since melphalan 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. Melphalan should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.

The 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.

Neutropenia and thrombocytopenia Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in elderly patients newly diagnosed with multiple myeloma, treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone.

8). 8). g. smoking, hypertension, hyperlipidaemia and history of thrombosis). These patients should be closely monitored and actions to minimize all modifiable risk factors should be undertaken. 2. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism.

Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, arm or leg swelling. If a patient experiences any thromboembolic events, discontinue the treatment immediately and initiate the standard anticoagulation therapy.

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 throughout the course of treatment. Renal impairment Melphalan clearance may be reduced in patients with renal impairment who may also have uraemic marrow suppression. 2). 8 for elevation of blood urea.

Patients with renal impairment should be closely monitored for signs/signals of overdose. Paediatric population There is no adequate experience for children. 2). Mutagenicity Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients treated with melphalan.

Carcinogenicity (Second primary malignancy) Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) Melphalan, 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 amyloidosis, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.

A comparison of patients with ovarian cancer, […]

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