Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2024 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
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.
See 6.6 Instructions for use/handling
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.
Melphalan clearance may be reduced in patients with renal impairment, who may also have uraemic bone marrow suppression. Dosage reduction may therefore be necessary (see Section 4.2 Posology and method of administration - Renal impairment), and these patients should be closely observed.
The use of high dose melphalan has the potential to cause acute kidney injury in patients, especially those with underlying renal impairment and potential risk factors for reduced renal function (e.g., concomitant use of nephrotoxic medications, amyloidosis etc).
Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
The evidence is growing that melphalan in common with other alkylating agents has been reported to be leukaemogenic, 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 amyloidosis, 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.
Before the start of the treatment, the leukaemogenic risk (AML and MDS) must be balanced against the potential therapeutic benefit in particular if the use of melphalan in combination with thalidomide or lenalidomide, and prednisone is considered as it has been shown that these combinations 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.
Ovulation inhibitory progesterone-only pills (i.e., desogestrel). Because of the increased risk of venous thromboembolism in patients with multiple myeloma, combined oral contraceptive pills are not recommended. If a patient is currently using combined oral contraception, she should switch to another effective and reliable contraceptive method. The risk of venous thromboembolism continues for 4−6 weeks after discontinuing combined oral contraception.
The recommended duration of contraception in females should be during treatment and for a period of six months following the cessation of treatment (see section 4.6).
Male patients should use effective and reliable contraceptive methods during treatment and for a period of three months following the cessation of treatment (see section 4.6).
Male patients should have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of melphalan treatment (see section 4.6).
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.
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4).
Nalidixic acid together with high-dose intravenous melphalan has caused deaths in paediatrics due to haemorrhagic enterocolitis.
In paediatric population, for the Busulfan-Melphalan regimen it has been reported that the administration of melphalan less than 24 hours after the last oral busulfan administration may influence the development of toxicities.
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.
Female patients should use effective and reliable contraceptive methods during treatment and for a period of six months, following the cessation of treatment.
Male patients should use effective and reliable contraceptive methods during treatment and for a period of three months following the cessation of treatment.
The final decision regarding the additional time period on contraception should be taken by the doctor and/or the patient (see section 4.4).
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.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Melphalan.
Mother receiving Melphalan should not breast-feed.
Melphalan causes suppression of ovarian function in premenopausal women resulting in amenorrhoea in a significant number of patients.
There is evidence from some animal studies that melphalan can have an adverse effect on spermatogenesis (see section 5.3). Therefore, it is possible that melphalan may cause temporary or permanent sterility in male patients. It is recommended that men who are receiving treatment with Melphalan have a consultation on sperm preservation before treatment due to the possibility of irreversible infertility as a result of Melphalan treatment (see section 4.4).
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.
Effects on the ability to drive and operate machinery in patients taking this medicine have not been studied.
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, not known (cannot be estimated from the available data).
| Body System | Frequency | Side Effects |
|---|---|---|
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | Not known | Secondary acute myeloid leukaemia and myelodysplastic syndrome (see section 4.4) |
| Blood and Lymphatic System Disorders | Very common | bone marrow depression leading to leucopenia, thrombocytopenia and anaemia |
| Rare | haemolytic anaemia | |
| Immune System Disorders | Rare | hypersensitivity1 (see Skin and Subcutaneous Tissue Disorders) |
| Respiratory, Thoracic and Mediastinal Disorders | Rare | interstitial lung disease and pulmonary fibrosis (including fatal reports) |
| Gastrointestinal Disorders | Very common | nausea2, vomiting2 and diarrhoea; stomatitis at high dose |
| Rare | stomatitis at conventional dose | |
| Hepatobiliary Disorders | Rare | liver 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 | rash maculo-papular and pruritus (see Immune System Disorders) | |
| Renal and Urinary Disorders | Common | blood urea increased3 |
| Not known | Acute kidney injury | |
| Reproductive system and breast disorders | Not known | azoospermia, amenorrhoea |
| Vascular Disorders4 | Not known | Deep vein thrombosis and pulmonary embolism |
| General Disorders and Administration Site Conditions | Very common | pyrexia |
1 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.
2 Gastrointestinal effects such as nausea and vomiting have been reported in up to 30% of patients receiving conventional oral doses of melphalan.
3 Temporary significant elevation of the blood urea has been commonly seen in the early stages of melphalan therapy in myeloma patients with renal damage.
4 The clinically important adverse reactions associated with the use of melphalan in combination with thalidomide and prednisone or dexamethasone and to a lesser extend melphalan with lenalidomide and prednisone include: deep vein thrombosis and pulmonary embolism (see sections 4.2 and 4.4).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
None known.
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