POM: Prescription only medicine
This information is intended for use by health professionals
Multiple Myleloma:Numerous regimes have been used and the scientific literature should be consulted for details. The administration of Melphalan and prednisone is more effective than Melphalan alone. The combination is usually given on an intermittent basis, although the superiority of this technique over continuous therapy is not established. A typical oral dosage schedule is 0.15 mg/kg bodyweight/day in divided doses for 4 days repeated at intervals of six weeks. Prolonging treatment beyond one year in responders does not appear to improve results.
Ovarian adenocarcinoma:A typical regimen is 0.2 mg/kg bodyweight/day orally for 5 days. This is repeated every 4-8 weeks, or as soon as the bone marrow has recovered. Melphalan has also been used intravenously in the treatment of ovarian carcinoma.Advanced carcinoma of the breast: Melphalan has been given orally at a dose of 0.15 mg/kg bodyweight or 6 mg/m2 body surface area/day for 5 days and repeated every 6 weeks. The dose was decreased if bone marrow toxicity was observed.
Polycythaemia vera:For remission induction the usual dose is 6-10 mg daily for 5-7 days, after which 2-4 mg daily is given until satisfactory disease control is achieved. Therapy is maintained with a dose of 2-6 mg per week. During maintenance therapy, careful haematological control is essential with dosage adjustment according to the results of frequent blood counts.
Children:Melphalan is very rarely indicated in children and dosage guidelines cannot be stated.
Use in the elderly:There is no specific information available on the use of Melphalan in elderly patients.
Dosage in renal impairment:In patients with moderate to severe renal impairment currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering the oral preparation to these patients, but it may be prudent to use a reduced dose initially.
Safe Handling of MELPHALAN tablets:See 6.6 Instructions for use/handling
Monitoring:Since Melphalan is a potent myelosuppresive 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 leucocyte 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.
Renal impairment:Patients with renal impairment should be closely observed as they may have uraemic marrow suppression. (See undesirable effects for elevation of blood urea Section 4.8)
Mutagenicity:Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
Carcinogenicity:The evidence is growing that 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 amyloid, malignant melanoma, 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.Melphalan causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.
Teratogenicity:The teratogenic potential of Melphalan has not been studied. In view of its mutagenic properties and structural similarity to known teratogenic compounds, it is possible that melphalan could cause congenital defects in the offspring of patients treated with the drug.
Pregnancy:The use of melphalan should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
Lactation:Mother receiving Melphalan should not breast-feed.
|Blood and Lymphatic System Disorders|
|Very common:||bone marrow depression leading to leucopenia, thrombocytopenia and anaemia|
|Immune System Disorders|
|Rare:||allergic reactions (see Skin and Subcutaneous Tissue Disorders)|
|Respiratory, Thoracic and Mediastinal Disorders|
|Rare:||interstitial pneumonitis and pulmonary fibrosis (including fatal reports)|
|Very common:||nausea, vomiting and diarrhoea; stomatitis at high dose|
|Rare:||stomatitis at conventional dose|
|Gastrointestinal effects such as nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of melphalan.|
|Rare:||hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice|
|Skin and Subcutaneous Tissue Disorders|
|Very common:||alopecia at high dose|
|Common:||alopecia at conventional dose|
|Rare:||maculopapular rashes and pruritus (see Immune System Disorders)|
|Renal and Urinary Disorders|
|Common:||temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage|
Symptoms and signs:Gastro-intestinal effects, including nausea, vomiting and diarrhoea are the most likely signs of acute oral overdosage. Diarrhoea, sometimes haemorrhagic, has been reported after intravenous overdosage. The principal toxic effect is bone marrow aplasia, leading to leucopoenia, thrombocytopenia and anaemia.
Treatment: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.General supportive measures, together with appropriate blood transfusion, should be instituted if necessary.
DistributionMelphalan displays limited penetration of the blood-brain barrier. Several investigators have sampled cerebrospinal fluid and found no measurable drug. Low concentrations (~10% of that in plasma) were observed in a single high-dose study in children. EliminationIn 13 patients given oral melphalan at 0.6 mg/kg bodyweight, the plasma mean terminal elimination half-life was 90 ± 57 min with 11% of the drug being recovered in the urine over 24 h.In 18 patients administered melphalan 0.2 to 0.25 mg/kg bodyweight orally, the mean elimination half-life was 1.12 ± 0.15 h. Special Patient Populations • Renal impairmentMelphalan clearance may be decreased in renal impairment (see Dosage and Administration - Renal impairment and Warnings and Precautions - Renal impairment). • ElderlyNo correlation has been shown between age and melphalan clearance or with melphalan terminal elimination half-life (see Dosage and Administration).
Safe handling of MELPHALAN tablets:The handling of Melphalan tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations (for example Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs).Provided the outer coating of the tablet is intact, there is no risk in handling Melphalan tablets.Melphalan tablets should not be divided.
Disposal:Melphalan tablets should be destroyed in accordance with relevant local regulatory requirements concerning the disposal of cytotoxic drugs.
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