MELPHALAN 2mg

Indications

• Multiple myeloma
• Ovarian cancer
• Localized malignant melanoma of the extremities
• Locally advanced breast cancer
• Polycythaemia vera

Mechanism of action

Melphalan is an alkylating agent of the bischloroethylamine type. It is believed to be taken up by tumour cells via a neutral amino acid active pathway shared by leucine. Melphalan binds at the N7 position of guanine and induces inter-strand cross-links in DNA, disrupting DNA synthesis or transcription. It can also cause DNA-protein cross-linking and induce lesions in RNA, proteins, and lipids. Melphalan is cytotoxic in resting and rapidly dividing tumour cells, interfering with DNA replication and transcription of RNA, ultimately disrupting nucleic acid function. It also possesses some immunosuppressive activity and is carcinogenic via a genotoxic mechanism.

Pharmacodynamics

Melphalan exhibits cytotoxic, immunosuppressive, and myeloablative activities. It produces chromosomal aberrations in vitro and in vivo, raising concerns about its potential leukemogenic effects in humans. The drug is known to cause dose-limiting bone marrow suppression. Following administration of melphalan 100 mg/m² for two consecutive days, a peak mean heart rate increase of 20 bpm was observed in multiple myeloma patients undergoing autologous stem cell transplantation, indicating potential cardiovascular effects.

Pharmacokinetics

Melphalan is administered orally or intravenously, with its absorption affected by food intake. The drug is extensively metabolized in the liver, and renal impairment may prolong its half-life and increase toxicity. The elimination half-life ranges from 30 minutes to 2 hours, depending on the route of administration and patient characteristics. Dose adjustments may be necessary in patients with renal impairment to mitigate the risk of toxicity.

Contra-indications

• Severe renal impairment
• Severe hepatic impairment
• Pregnancy
• Breastfeeding

Adverse effects

• Thrombocytopenia
• Multi-organ failure
• Urothelial toxicity
• Vision loss (irreversible)
• Stomatitis
• Vomiting
• Myocardial infarction
• Nephritis
• Neuropathy
• Pulmonary hypertension
• Acute leukaemias
• Tumour lysis syndrome
• Mucositis
• Pain
• Pancreatitis
• Panic attacks
• Peripheral neuropathy
• Vertigo
• Urinary disorders
• Ovarian and fallopian tube toxicity

Interactions

• Increased risk of toxicity with other cytotoxic drugs
• Potentially increased risk of acute leukaemia with ifosfamide
• Concurrent use with nephrotoxic agents may enhance renal toxicity

Precautions

• Monitor electrolyte balance and renal function before each course of treatment
• Ensure effective contraception during treatment and for at least 6 months after
• Risk of bone marrow suppression, requiring regular blood counts
• Use caution in patients with a history of psychiatric disorders

Pregnancy

Avoid due to teratogenic and carcinogenic potential in animal studies.

Breast-feeding

Discontinue breastfeeding during treatment.

Storage

Store in a cool, dry place away from light. Follow specific product storage instructions.

Formulations

• Melphalan 2 mg tablets
• Melphalan 5 mg tablets
• Melphalan 10 mg tablets
• Melphalan 50 mg vials for injection
• Melphalan 100 mg vials for injection

Mechanism of action

Melphalan is an alkylating agent of the bischloroethylamine type. It is believed to be taken up by tumour cells via a neutral amino acid active pathway shared by leucine. Melphalan binds at the N7 position of guanine and induces inter-strand cross-links in DNA, disrupting DNA synthesis or transcription. It can also cause DNA-protein cross-linking and induce lesions in RNA, proteins, and lipids. Melphalan is cytotoxic in resting and rapidly dividing tumour cells. Melphalan, as an alkylating agent, interferes with DNA replication and transcription of RNA, and ultimately results in the disruption of nucleic acid function. Melphalan also possesses some immunosuppressive activity. Melphalan is a direct-acting alkylating agent that is carcinogenic via genotoxic mechanism.

Pharmacodynamics

Melphalan possesses cytotoxic, immunosuppressive, and myeloablative activities. Melphalan produces chromosomal aberrations _in vitro_ and _in vivo_; thus, it is considered to be potentially leukemogenic in humans. It also causes dose-limiting bone marrow suppression. The peak mean heart rate increased by 20 bpm from baseline following melphalan 100 mg/m² for two consecutive days in multiple myeloma patients undergoing autologous stem cell transplantation.