Special Warning : אזהרת שימוש

4.4. Special warnings and precautions for use

Melphalan is a cytotoxic drug, which falls into the general class of alkylating agents.
Melphalan should be administered under the direction of a specialist oncology service having the facilities for a regular monitoring of clinical biochemical and haematological effects during and after administration. In view of the hazards involved and the level of supportive care required, the administration of high-dose melphalan Injection should only be conducted by experienced clinicians.
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.
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.
Since melphalan is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary.
Melphalan can cause local tissue damage, should extravasation occur and consequently, it should not be administered by direct injection into a peripheral vein.
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 should be used with caution in patients who have undergone recent radiotherapy or chemotherapy in view of increased bone marrow toxicity.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be practiced when receiving melphalan, up to three months for male patients and 6 months for female patients after end of treatment. For ovarian cancer, non- hormonal contraceptive methods are advised.
Monitoring
Bone marrow depression, with leucopenia and thrombocytopenia, is the main side effect. The time of maximum depression is variable, and careful attention should be paid to the monitoring of blood counts, both during and after treatment, to avoid the possibility of excessive myelosuppression and 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.


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.
Thromboembolic events
Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of deep vein thrombosis and pulmonary embolism (see section 4.8). The risk appears to be greatest during the first 5 months of therapy, especially in patients with additional thrombotic risk factors (e.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.
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.
Neutropenia and thrombocytopenia
Elderly
Increased rate of haematological toxicities, particularly, neutropenia and thrombocytopenia, was observed in newly diagnosed elderly multiple myeloma in patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone. Patients and physicians are advised to be observant for signs and symptoms of bleeding, including petechiae and epistaxes, especially in patients receiving combination drug regimens described (section 4.8).
Mutagenicity
Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
Melphalan has also been shown to be carcinogenic in animals (section 5.3), and the possibility of a similar effect should be borne in mind when designing the long-term management of the patient.
Suppression of ovarian function with resultant amenorrhoea occurs in a significant number of pre-menopausal patients.
There is evidence from some animal studies that melphalan can have an adverse effect on spermatogensis. Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients.
Carcinogenicity
Acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS)
Melphalan, in common with other alkylating agents, has been reported to be leukaemogenic in man, especially in older patients after long combination therapy and radiotherapy.
There have been reports of acute leukaemia occurring after melphalan treatment for diseases such as amyloid, malignant melanoma, multiple myeloma, macroglobulinaemia, cold agglutinin syndrome and ovarian cancer.
A comparison of patients with ovarian cancer who received alkylating agents with those who did not, showed that the use of alkylating agents, including melphalan, significantly increased the incidence of acute leukaemia.
The leukaemogenic risk must be balanced against the potential therapeutic benefit when considering the use of melphalan especially if the use of melphalan in combination with thalidomide or lenalidomide and prednisone is considered, as it has been shown that these combinations may increase the leukaemogenic risk. Before, during and after treatment doctors must therefore examine the patient at all times by usual measurements to ensure the early detection of cancer and initiate treatment if necessary.
Solid tumours
Use of alkylating agents has been linked with the development of second primary malignancy (SPM). In particular, melphalan in combination with lenalidomide and prednisone and, to a lesser extent, thalidomide and prednisone has been associated with the increased risk of solid SPM in elderly newly diagnosed multiple myeloma patients.
Patient characteristics (e.g. age, ethnicity), primary indication and treatment modalities (e.g. radiation therapy, transplantation), as well as environmental risk factors (e.g. tobacco use) should be evaluated prior to melphalan administration.
Risk must be balanced against the potential therapeutic benefit when considering the use of melphalan.
Contraception
Due to an increased risk of venous thromboembolism in patients undergoing treatment with melphalan in combination with lenalidomide and prednisone or in combination with thalidomide and prednisone or dexamethasone, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception, she should switch to another reliable contraceptive method (i.e. ovulation inhibitory progesterone-only pills such as desogestrel, barrier method etc). The risk of venous thromboembolism continues for 4-6 weeks after discontinuing combined oral contraception.
Renal Impairment
In patients with moderate to severe renal impairment the initial dose of the intravenous preparation should be reduced by 50% being determined thereafter according to haematological response. Such patients should be closely observed for uraemic marrow suppression. Temporary significant elevation of blood urea has been seen in the early stages of treatment in myeloma patients with renal damage (see sections 4.2 and 4.8).
iImportant information about other components:
5% Ethanol (alcohol)
This medicine contains 0.424g of alcohol (ethanol) in each 10 ml vial which is equivalent to 7.1 mg/kg (4.24% w/v).
The amount in 10 ml of this medicine is equivalent to less than 11 ml beer or 4 ml wine.
The small amount of alcohol in this medicine will not have any noticeable effects.
Propylene glycol
Propylene glycol in this medicine can have the same effects as drinking alcohol and increase the likelihood of side effects.
Do not use this medicine in children less than 5 years old.
Use this medicine only if recommended by a doctor. Your doctor may carry out extra checks while you are taking this medicine.
Sodium
This medicinal product contains 53.50 mg sodium per vial, equivalent to 2.7% of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Seven vials reflect the lowest number of vials for which the threshold of 17 mmol (391 mg) of sodium is reached/ exceeded.

Effects on Driving

4.7 Effects on ability to drive and use machines
No studies have been conducted on the effects on the viability and the ability to operate machines. However the possibility will have to be taken into consideration, that the alcohol quantity in these pharmaceutical medicinal product can impair the competency to drive and the ability to operate machines.