Chemical formula: C₁₃H₁₈Cl₂N₂O₂ Molecular mass: 305.2 g/mol PubChem compound: 460612
Melphalan interacts in the following cases:
Melphalan clearance, though variable, may be decreased in renal impairment.
Currently available pharmacokinetic data do not justify an absolute recommendation on dosage reduction when administering melphalan to patients with renal impairment, but it may be prudent to use a reduced dosage initially until tolerance is established. When melphalan is used at conventional intravenous dosage (8-40 mg/m² body surface area), it is recommended that the initial dose should be reduced by 50% and subsequent dosage determined according to the degree of haematological suppression.
For high intravenous doses of melphalan (100 to 240 mg/m² body surface area), the need for dose reduction depends upon the degree of renal impairment, whether haematopoietic stem cells are re-infused, and therapeutic need. As a guide, for high dose melphalan treatment without haematopoietic stem cell rescue in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) a dose reduction of 50% is usual.
High dose melphalan with haematopoietic stem cell rescue has been used successfully even in dialysis dependent patients with end-stage renal failure. The relevant literature should be consulted for details.
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. 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.
Patients treated with melphalan in combination with lenalidomide and prednisone or thalidomide and prednisone or dexamethasone, have an increased risk of thromboembolic events. Especially in patients with additional thrombotic risk factors antithrombotic prophylactic measures should be considered.
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.
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.
There are no or limited amount of data from the use of melphalan in pregnant women. Studies in animals have shown reproductive toxicity. 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.
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.
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. 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.
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
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.
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