Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Sun Pharmaceutical Industries Europe B.V., Polarisavenue 87, 2132 JH Hoofddorp, The Netherlands
Melphalan is a cytotoxic drug, which falls into the general class of alkylating agents. It should be prescribed only by physicians experienced in the management of malignant disease with such agents. As with all high dose chemotherapy, precautions should be taken to prevent tumour lysis syndrome.
Immunization using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunizations 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 either partner is receiving melphalan up to three months after end of treatment. For ovarian cancer, non-hormonal contraceptive methods are advised.
Since melphalan is a potent myelosuppressive 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 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.
Melphalan clearance may be reduced in patients with renal impairment who may also have uraemic marrow suppression. Dose reduction may therefore be necessary (see section 4.2). See section 4.8 for undesirable effects for elevation of blood urea. Patients with renal impairment should be closely monitored for signs/signals of overdose.
Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of thromboembolic events (see section 4.8). Especially in patients with additional thrombotic risk factors antithrombotic prophylactic measures should be considered (see sections 4.2 and 4.8).
Melphalan is mutagenic in animals and chromosome aberrations have been observed in patients being treated with the drug.
Melphalan has been reported to be leukaemogenic. 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.
This medicinal product contains 5% ethanol (alcohol), equivalent to 10 ml beer or 2.4 ml wine. Harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.
This medicinal product contains propylene glycol. May cause alcohol-like symptoms.
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 children due to haemorrhagic entercolitis. Combined treatment of melphalan with nalidixic acid should be avoided.
In the 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 received high dose intravenous melphalan and who subsequently received ciclosporin to prevent graft-versus-host disease.
As with all cytotoxic treatments, male and female patients who use Melphalan should use effective and reliable contraceptive methods up until three months after cessation of treatment. The use of hormonal contraceptives should be avoided in ovarian cancer.
There are no or limited amount of data from the use of melphalan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Risk for human is not known, but due to the mutagenic properties and structural similarity of melphalan with known teratogenic compounds, it is possible that melphalan can induce congenital malformations in offspring of treated patients. Melphalan should not be used during pregnancy unless the clinical condition of the woman requires treatment with melphalan.
It is unknown whether melphalan or its metabolites are excreted in human milk. Due to its mutagenic properties, Melphalan is contraindicated during breastfeeding (see section 4.3).
Melphalan causes suppression of ovary function in premenopausal women, resulting in amenorrhea in a large number of patients.
Studies in animals have shown melphalan can have adverse effects on spermatogenesis (see section 5.3). Therefore it is possible that melphalan may cause temporary or permanent adverse effects on male fertility. It is recommended that men who are receiving treatment with melphalan not father a child during treatment and up to 3 months afterwards. Cryopreservation of semen before treatment is advised.
There are no data regarding the effect of melphalan treatment on the ability to drive and use machines. Based on the pharmacological profile such an effect is not anticipated. When advising patients treated for malignant disease it is recommended to consider their general health status.
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 utilized for the classification of frequency: very common ≥1/10, common ≥1/100 and <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).
Not known: secondary acute myeloid leukaemia and myelodysplastic syndrome (see section 4.4)
Very common: bone marrow depression leading to leucopenia, thrombocytopenia, neutropenia and anaemia
Rare: haemolytic anaemia
Rare: allergic reactions1 (see skin and subcutaneous tissue disorders)
Rare: interstitial pneumonitis and pulmonary fibrosis (including fatal reports)
Very common: nausea, vomiting and diarrhea, stomatitis at high dose
Rare: stomatitis at conventional dose
Rare: heptatic disorders ranging from abnormal liver function tests to clinical manifestations such as hepatitis and jaundice; veno-occlusive disease following high dose treatment
Very common: alopecia at high dose
Common: alopecia at conventional dose
Rare: maculopapular rashes and pruritus (see immune system disorders)
Very common: muscle atrophy, muscle fibrosis, myalgia, blood creatine phosphokinase increased
Common: compartment syndrome
Not known: muscle necrosis, rhabdomyolysis
Common: blood urea increased3
Not known: azoospermia, amenorrhoea
Not known: deep vein thrombosis and pulmonary embolism
Very common: subjective and transient sensation of warmth and/or tingling
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 Only with melphalan infusion after administration of regional perfusion in the limb
3 Temporary significant elevation of the blood urea has been 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 authorization 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
Melphalan is not compatible with infusion solutions containing dextrose, and it is recommended that ONLY Sodium Chloride Intravenous Infusion 0.9% w/v is used.
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