Drug Class Description
Alkylating agents (cytotoxics).

Generic Name
Melphalan Glaxo Wellcome is discontinuing Alkeran 5mg tablets when existing stocks are exhausted. This is estimated to occur by the summer of 2001.

Drug Description
Each tablet contains 2 mg melphalan.

Presentation
Film-coated tabletsALKERAN are white to off-white film-coated, round, biconvex tablets engraved “GX EH3” on one side and “A” on the other.

Indications
Alkeran Tablets are indicated in the treatment of multiple myeloma and advanced ovarian adenocarcinoma.Alkeran either alone or in combination with other drugs has a significant therapeutic effect in a proportion of patients suffering from advanced breast carcinoma. Alkeran is effective in the treatment of a proportion of patients suffering from polycythaemia vera.

Adult Dosage
Since Alkeran is myelosuppressive, frequent blood counts are essential during therapy and the dosage should be delayed or adjusted if necessary.Oral administration in Adults: The absorption of Alkeran after oral administration is variable. Dosage may need to be cautiously increased until myelosuppresion is seen, in order to ensure that potentially therapeutic levels have been reached.Multiple Myleloma: Numerous regimes have been used and the scientific literature should be consulted for details. The administration of Alkeran and prednisone is more effective than Alkeran 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. Alkeran has also been used intravenously in the treatment of ovarian carcinoma.Advanced carcinoma of the breast:Alkeran 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.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.

Child Dosage
Alkeran is very rarely indicated in children and dosage guidelines cannot be stated.

Elderly Dosage
There is no specific information available on the use of Alkeran in elderly patients.

Contra Indications
Alkeran should not be given to patients who have suffered a previous hypersensitivity reaction to melphalan

Special Precautions
Alkeran is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.Monitoring: Since Alkeran 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. Alkeran 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.Mutagenicity:Alkeran 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.Alkeran causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.

Interactions
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Warnings and Precautions).Nalidixic acid together with high-dose intravenous melphalan has caused deaths in children due to haemorrhagic enterocolitis.Impaired renal function has been described in bone marrow transplant patients who were pre-conditioned with high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.

Adverse Reactions
For this 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.The following convention has been utilised for the classification of frequency:- Very common 1/10, common 1/100, <1/10, uncommon 1/1000 and <1/100, rare 1/10,000 and <1/1000, very rare <1/10,000.Blood and Lymphatic System DisordersVery common: bone marrow depression leading to leucopenia, thrombocytopenia and anaemiaRare: haemolytic anaemiaImmune System DisordersRare: allergic reactions (see Skin and Subcutaneous Tissue Disorders)Allergic reactions to melphalan such as urticaria, oedema, skin rashes and anaphylactic shock have been reported uncommonly following initial or subsequent dosing, particularly after intravenous administration. Cardiac arrest has also been reported rarely in association with such events.Respiratory, Thoracic and Mediastinal DisordersRare: interstitial pneumonitis and pulmonary fibrosis (including fatal reports)Gastrointestinal DisordersVery common: nausea, vomiting and diarrhoea; stomatitis at high doseRare: stomatitis at conventional doseGastrointestinal effects such as nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of melphalan.Hepatobiliary DisordersRare: hepatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundiceSkin and Subcutaneous Tissue DisordersVery common: alopecia at high doseCommon: alopecia at conventional doseRare: maculopapular rashes and pruritus (see Immune System Disorders)Renal and Urinary DisordersCommon: temporary significant elevation of the blood urea has been seen in the early stages of melphalan therapy in myeloma patients with renal damage

Manufacturer
GlaxoSmithKline(GSK)

Drug Availability
(POM)

Updated
04 June 2009