MELPHALAN Film-coated tablets Ref.[8200] Active ingredients: Melphalan

Melphalan 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.

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.

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.

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Melphalan.

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.

Not known.

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 Disorders

Very common: bone marrow depression leading to leucopenia, thrombocytopenia and anaemia

Rare: haemolytic anaemia

Immune System Disorders

Rare: 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 Disorders

Rare: interstitial pneumonitis and pulmonary fibrosis (including fatal reports)

Gastrointestinal Disorders

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.

Hepatobiliary Disorders

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

None known.