MELPHALAN

Clinical safety rating: avoid

Contraindicated (not allowed)

How it works

Melphalan is an alkylating agent that forms interstrand crosslinks with DNA, inhibiting DNA replication and transcription, leading to cell death.

What the body does with it

Metabolism	Melphalan undergoes spontaneous hydrolysis to form monohydroxy and dihydroxy metabolites; also metabolized by CYP450 enzymes (minor pathway).
Excretion	Renal: 10-15% unchanged; hepatic metabolism (20-30%) with biliary excretion of metabolites; fecal: <5%.
Half-life	Terminal half-life: 1.5-2 hours (IV); prolonged in renal impairment (up to 3-4 hours).
Protein binding	60-90%, primarily to albumin; alpha-1-acid glycoprotein to a lesser extent.
Volume of Distribution	0.5-0.6 L/kg (IV); indicates extensive tissue distribution (e.g., tumor, marrow).
Bioavailability	Oral: 25-30% (high interpatient variability; food reduces absorption).
Onset of Action	IV: 1-2 weeks (cytoreduction); oral: 2-3 weeks (therapeutic effect).
Duration of Action	Approximately 4-6 weeks (myelosuppression recovery); oral: nadir at 4-6 weeks.

Classification & Brands

Dosing & administration

Melphalan 0.25 mg/kg/day orally for 4 consecutive days, repeated every 4-6 weeks; or 16 mg/m² intravenously over 15-20 minutes at 2-week intervals for 4 doses.

Dosage form	TABLET
Renal impairment	For IV melphalan: CrCl 10-50 mL/min: reduce dose by 50%; CrCl <10 mL/min: administer 25% of normal dose. For oral melphalan: CrCl <30 mL/min: consider reducing dose by 50%.
Liver impairment	Child-Pugh Class A: no adjustment; Child-Pugh Class B: reduce dose by 50%; Child-Pugh Class C: contraindicated or reduce dose by 75% with close monitoring.
Pediatric use	For multiple myeloma or neuroblastoma: 0.1-0.15 mg/kg orally daily for 2-3 weeks, then adjust based on blood counts. For conditioning regimens: IV 140-210 mg/m² over 2 days with stem cell support.
Geriatric use	Monitor renal function closely; consider dose reduction for CrCl <50 mL/min; increased risk of myelosuppression; initiate at lower end of dosing range.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and secondary malignancies.

Breastfeeding	Melphalan is excreted into breast milk in low amounts; M/P ratio not established. Due to potential for severe adverse effects (myelosuppression, carcinogenesis), breastfeeding is contraindicated during therapy and for at least 2 weeks after the last dose.
Teratogenic Risk	FDA Pregnancy Category D. First trimester: High risk of congenital malformations including skeletal and CNS defects. Second and third trimesters: Fetal growth restriction, myelosuppression, and increased risk of neonatal pancytopenia. Avoid use in pregnancy unless no safer alternative.

Warnings & precautions

■ FDA Black Box Warning

Melphalan is highly myelosuppressive, causing severe bone marrow suppression, including neutropenia, thrombocytopenia, and anemia. It is associated with an increased risk of secondary malignancies, particularly acute myeloid leukemia and myelodysplastic syndrome.

Side Effect Profile

Common Effects	other cancers
Serious Effects

Absolute Contraindications

Hypersensitivity to melphalan; severe bone marrow suppression (unless expected benefit outweighs risk); breastfeeding.

Clinical Precautions

Precautions

Severe myelosuppression; increased risk of secondary leukemia; hypersensitivity reactions; extravasation risk; impaired renal function may require dose adjustment; pregnancy category D; use with caution in patients with prior radiation or chemotherapy.

Clinical Tips & Counseling

Drug interactions

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