MELPHALAN HYDROCHLORIDE
Clinical safety rating: avoid
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and secondary malignancies.
Melphalan is a bifunctional alkylating agent that forms cross-links between DNA strands, inhibiting DNA replication and transcription. It is cell cycle phase-nonspecific.
| Metabolism | Melphalan undergoes rapid hydrolysis in plasma to mono- and dihydroxy metabolites. Minor hepatic metabolism via cytochrome P450 (CYP2B6, CYP2C8, CYP3A4) but hydrolysis is the primary pathway. |
| Excretion | Renal: 10-30% unchanged; fecal: 20-30% as metabolites; biliary: minor. |
| Half-life | 1.5-2.5 h (terminal) in normal renal function; may be prolonged in renal impairment. |
| Protein binding | 60-90% bound, primarily to albumin. |
| Volume of Distribution | 0.5-0.6 L/kg; distributes to total body water with some tissue binding. |
| Bioavailability | Oral: 25-30% with high interpatient variability; IV: 100%. |
| Onset of Action | IV: 2-4 weeks for multiple myeloma; oral: 4-6 weeks. |
| Duration of Action | 3-6 weeks; myelosuppression nadir at 4-6 weeks, recovery at 6-8 weeks. |
| Molecular Weight | 342.26 Da |
16 mg/m² intravenously over 15-20 minutes every 2 weeks for 4 doses, then every 4 weeks
| Dosage form | INJECTABLE |
| Renal impairment | CrCl >50 mL/min: 100% dose; CrCl 10-50 mL/min: 75% dose; CrCl <10 mL/min: 50% dose |
| Liver impairment | Child-Pugh A: 100% dose; Child-Pugh B: 75% dose; Child-Pugh C: 50% dose |
| Pediatric use | 10-25 mg/m² orally once daily for 4-7 days every 4-6 weeks; adjust based on toxicity |
| Geriatric use | Reduce initial dose by 25% due to increased toxicity; monitor renal function and hematologic parameters |
| 1st trimester | Contraindicated due to teratogenicity; avoid. If exposure occurs, high risk of miscarriage and malformations. |
| 2nd trimester | Contraindicated; may cause fetal harm. Use only if clearly needed and no alternative. |
| 3rd trimester | Contraindicated; potential for neonatal myelosuppression and other adverse effects. |
Clinical note
Other bone marrow suppressants may have additive effects Can cause severe myelosuppression and secondary malignancies.
| FDA category | Contraindicated |
| Placental transfer | Melphalan crosses the placenta as demonstrated in animal studies and human case reports; extent of transfer is moderate but clinically significant. |
| Breastfeeding |
■ FDA Black Box Warning
WARNING: Melphalan should be administered under the supervision of a qualified physician experienced in cancer chemotherapy. Severe bone marrow suppression with resulting infection or bleeding may occur. Melphalan is leukemogenic in humans. Monitor blood counts frequently.
| Common Effects | other cancers |
| Serious Effects |
History of hypersensitivity to melphalan or any component of the formulationPatients with severe myelosuppression (e.g., ANC < 1000/mm3, platelet count < 75,000/mm3) unless for purpose of bone marrow ablationPregnancy (teratogenic)
| Precautions | Bone marrow suppression (dose-limiting toxicity), Hypersensitivity reactions (including anaphylaxis), Secondary malignancies (especially acute leukemia), Myelosuppression exacerbated by renal impairment, Carcinogenicity and mutagenicity, Embryo-fetal toxicity, Vaccination risks with live vaccines |
| Food/Dietary |
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| Excreted into breast milk; potential for serious adverse reactions in nursing infant. Breastfeeding is not recommended during therapy and for at least 1 week after last dose. |
| Lactation Rating | L5 - Contraindicated |
| Teratogenic Risk | Melphalan is a DNA alkylating agent with known teratogenic potential. Exposure during the first trimester is associated with major congenital malformations, including neural tube defects, skeletal anomalies, and growth restriction. During the second and third trimesters, it may cause fetal myelosuppression, intrauterine growth restriction, and low birth weight. Use during pregnancy is contraindicated unless maternal benefit justifies fetal risk. |
| Fetal Monitoring | Baseline and serial complete blood counts (CBC) with differential to monitor myelosuppression. Liver function tests (LFTs) and renal function tests (serum creatinine, BUN) prior to each cycle. Fetal monitoring includes serial ultrasound for growth assessment and anatomy survey in the second trimester. Assess for signs of intrauterine growth restriction, oligohydramnios, or hydrops. |
| Fertility Effects | Melphalan is gonadotoxic. It can cause amenorrhea, ovarian failure, and premature ovarian insufficiency in women. In men, it may cause azoospermia or oligospermia with potential for permanent infertility. Effects are dose- and age-dependent. Pre-treatment fertility preservation counseling is strongly recommended for patients of reproductive potential. |
| Food significantly reduces the oral bioavailability of melphalan. Administer on an empty stomach: at least 1 hour before or 2 hours after a meal. Avoid grapefruit juice as it may alter metabolism via CYP3A4 inhibition? No specific interaction documented; caution is advised. No other significant food interactions known. |
| Clinical Pearls | Melphalan hydrochloride is an alkylating agent used primarily in multiple myeloma and ovarian cancer. Administer with caution in renal impairment; dose reduction is required for severe renal dysfunction (CrCl <30 mL/min). Prehydration and monitoring of urine output are essential to prevent hemorrhagic cystitis, especially with high-dose regimens. Avoid concurrent use with other nephrotoxic agents. Myelosuppression is dose-limiting; monitor CBC regularly. Use in patients with prior radiation therapy may increase myelosuppression. In multiple myeloma, the combination with prednisone is standard. |
| Patient Advice | Take melphalan exactly as prescribed, usually once daily for 5 days every 4 to 6 weeks. · Take on an empty stomach (at least 1 hour before or 2 hours after a meal) to enhance absorption. · Avoid prolonged sun exposure; use sunscreen and protective clothing as melphalan can cause photosensitivity. · Report any signs of infection (fever, sore throat), unusual bleeding or bruising, or mouth sores immediately. · Drink plenty of fluids to reduce the risk of bladder irritation, especially in high-dose therapy. · Women of childbearing potential should use effective contraception during treatment and for at least 6 months after completion. · Breastfeeding is not recommended during melphalan therapy. · Do not receive live vaccines while on melphalan; consult your healthcare provider before any vaccination. |