ALKERAN 2MG Film-coated tablet

Alkeran is a potent cytotoxic medicinal product intended for use under the supervision of physicians experienced in the administration of such agents. Immunisation with live vaccines may potentially cause infection in immunocompromised patients.‍​‍‍‍​‍‍‍‍‍‍‍‍​‍ Therefore, immunisation with live vaccines is not recommended in patients treated with Alkeran. Thromboembolic events Treatment with melphalan in combination with lenalidomide and prednisone, or 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, particularly in patients with additional thrombotic risk factors. The decision to use antithrombotic prophylactic measures should follow careful assessment of underlying risk factors in individual patients (see sections 4.4 and 4.8 ). If a thromboembolic event occurs in a patient, treatment must be discontinued and standard anticoagulation therapy initiated. Once the patient has been stabilised on anticoagulation therapy 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 resumed at the original dose and regimen. The patient should continue anticoagulation therapy during treatment with melphalan. Monitoring Since Alkeran is a strongly myelosuppressive agent, careful attention must be paid to frequent regular blood count monitoring to avoid the possibility of excessive myelosuppression and the risk of irreversible bone marrow aplasia. Blood counts may continue to fall after discontinuation of Alkeran; therefore, its use should be temporarily interrupted at the first signs of an abnormally large decrease in leucocyte or platelet counts. Special caution is required when using Alkeran in patients who have recently undergone other chemotherapy or radiotherapy, owing to increased myelotoxicity. Renal impairment Melphalan clearance may be reduced in patients with renal dysfunction, in whom uraemic bone marrow suppression may occur. This may require dose reduction (see section 4.2 ), and these patients must be carefully monitored. Use of high-dose melphalan may cause acute kidney injury, particularly in patients with pre-existing renal impairment and potential risk factors for decreased renal function (e.g. concomitant use of nephrotoxic medicines, amyloidosis, etc.). A transient significant rise in blood urea concentration has been observed during the early stages of melphalan therapy in patients with multiple myeloma and renal impairment. Mutagenicity Chromosomal aberrations have been observed in patients treated with this medicinal product. Carcinogenicity (second primary malignancy) Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) Leukaemogenic effects have been reported with melphalan, as with other alkylating agents, particularly in elderly patients following long-term combination therapy and radiotherapy. The development of acute leukaemia has been reported following melphalan therapy for amyloidosis, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian carcinoma. A comparison of patients with ovarian carcinoma who were treated with alkylating agents with patients with the same diagnosis who were not treated with such agents showed that the use of alkylating agents (including melphalan) significantly increased the incidence of acute leukaemia. Before initiating treatment, the leukaemogenic risks (AML and MDS) must be weighed against the potential therapeutic benefit, particularly when the use of melphalan in combination with thalidomide or lenalidomide and prednisone is being considered, as these combinations have been shown to increase the leukaemogenic risk. Solid tumours The use of alkylating agents has been associated with the development of second primary malignancies (SPM). In particular, the use of melphalan in combination with lenalidomide and prednisone and, to a lesser extent, with thalidomide and prednisone has been associated with an increased risk of solid SPM in elderly patients with newly diagnosed multiple myeloma. Patient characteristics (e.g. age, ethnicity), primary indication and treatment modalities (e.g. radiation therapy, transplantation), as well as lifestyle risk factors (e.g. tobacco use) should be evaluated before administering melphalan. Contraception Due to the increased risk of venous thromboembolism in patients undergoing treatment with melphalan in combination with lenalidomide and prednisone, or thalidomide and prednisone, or dexamethasone, the use of combined oral contraceptives is not recommended. If a patient is currently taking combined oral contraceptives, she should switch to another effective and reliable method of contraception. The risk of venous thromboembolism persists for 4–6 weeks after discontinuation of combined oral contraceptives. Women are advised to use contraception during treatment and for six months after its completion (see section 4.6 ). Male patients should use effective and reliable contraceptive methods during treatment and for three months after its completion (see section 4.6 ). Fertility Due to the possibility of irreversible infertility resulting from melphalan treatment, male patients should be counselled about sperm preservation before starting treatment (see section 4.6 ).