MELPHALAN
Clinical safety rating: avoid
Contraindicated (not allowed)
Melphalan is an alkylating agent that forms interstrand crosslinks with DNA, inhibiting DNA replication and transcription, leading to cell death.
| 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. |
| Molecular Weight | 305.2 |
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. |
| 1st trimester | Melphalan is contraindicated in the first trimester due to teratogenicity; avoid use unless no safer alternative. |
| 2nd trimester | May cause fetal harm; use only if clearly needed and no safer alternative exists. |
| 3rd trimester | May cause fetal harm and neonatal toxicity; avoid use near term. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and secondary malignancies.
| Placental transfer | Melphalan crosses the placenta; detectable in cord blood. |
| Breastfeeding | Melphalan is excreted into breast milk in low concentrations. Due to potential serious adverse reactions in the nursing infant, women should not breastfeed during treatment and for at least 2 weeks after the last dose. |
■ 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.
| Common Effects | other cancers |
| Serious Effects |
Hypersensitivity to melphalanSevere bone marrow suppression (ANC < 1.5 x 10^9/L)Breastfeeding
| 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. |
| Food/Dietary | No significant food interactions reported. Avoid grapefruit juice as it may affect melphalan metabolism (theoretical based on CYP450 interaction). |
Loading safety data…
| Lactation Rating |
| L5 (Contraindicated) |
| 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. |
| Fetal Monitoring | Monitor maternal complete blood count (CBC) with differential, renal function, and liver function tests weekly. Fetal ultrasound for growth restriction and anomalies. Consider fetal echocardiography if exposure occurs in first trimester. |
| Fertility Effects | Melphalan causes dose-dependent gonadal toxicity. In premenopausal women, it may induce ovarian failure and premature menopause; in men, it can cause oligospermia or azoospermia, which may be irreversible. Fertility preservation counseling is recommended before treatment. |
| Clinical Pearls | Administer with caution in renal impairment; reduce dose if CrCl < 40 mL/min. Pre-hydrate to prevent tumor lysis syndrome. Monitor CBC weekly due to myelosuppression (nadir at 2-3 weeks). Can cause hypersensitivity reactions, including anaphylaxis. IV formulation requires use of a 0.45 μm filter due to particulate formation. |
| Patient Advice | This drug can lower your blood cell counts, increasing risk of infection, bleeding, and fatigue. · Avoid live vaccines during treatment and for 3 months after. · Report any signs of infection (fever, chills) or unusual bleeding/bruising immediately. · Use effective contraception during and for at least 6 months after therapy. · Drink plenty of fluids to prevent tumor lysis syndrome. |