HEPZATO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for HEPZATO (HEPZATO).
HEPZATO (melphalan) is a nitrogen mustard alkylating agent that crosslinks DNA strands, inhibiting DNA replication and transcription, leading to cell death.
| Metabolism | Primarily hydrolyzed spontaneously to monohydroxymelphalan and dihydroxymelphalan; also undergoes hepatic metabolism via cytochrome P450 enzymes. |
| Excretion | HEPZATO (melphalan hydrochloride) for injection is renally eliminated; approximately 20-30% of the administered dose is excreted unchanged in the urine over 24 hours. The major metabolites are hydrolysis products, which are also excreted renally. Biliary/fecal elimination accounts for less than 10% of the dose. |
| Half-life | The terminal elimination half-life of melphalan is approximately 1.5 hours following intravenous administration. This short half-life necessitates regional delivery (hepatic arterial infusion) to achieve high local concentrations with limited systemic exposure. |
| Protein binding | Approximately 60-90% of melphalan is bound to plasma proteins, primarily albumin. Binding is concentration-dependent and decreases at higher drug concentrations. |
| Volume of Distribution | The volume of distribution at steady state (Vdss) for melphalan is approximately 0.5 L/kg, indicating distribution into total body water and moderate tissue binding. This moderate Vd reflects limited extravascular distribution due to rapid hydrolysis and protein binding. |
| Bioavailability | HEPZATO is administered via hepatic arterial infusion; systemic bioavailability following intra-arterial administration is 100% for the delivered dose, but the hepatic first-pass extraction is high, resulting in a systemic exposure that is approximately 20-30% of the dose. Oral bioavailability is not applicable as the drug is only approved for intra-arterial use. |
| Onset of Action | After intravenous administration, melphalan acts as an alkylating agent with cytotoxic effects occurring within minutes to hours as it forms cross-links with DNA. Clinical antitumor effect is typically observed within 2-4 weeks following treatment cycles. |
| Duration of Action | The alkylation of DNA is irreversible, leading to cell death during replication. The duration of myelosuppression, a key dose-limiting toxicity, is typically 3-4 weeks, with nadir at 2-3 weeks, and recovery by week 4-6. |
Melphalan 3 mg/kg ideal body weight via hepatic artery infusion over 15-30 minutes followed by hemofiltration, administered once per treatment cycle.
| Dosage form | POWDER |
| Renal impairment | Contraindicated if CrCl < 30 mL/min. For CrCl 30-60 mL/min, reduce dose by 50%. No adjustment for CrCl > 60 mL/min. |
| Liver impairment | Contraindicated in Child-Pugh class C. For Child-Pugh class B, reduce dose by 50%. No adjustment for Child-Pugh class A. |
| Pediatric use | Safety and efficacy not established in pediatric patients; no specific dosing recommendations available. |
| Geriatric use | No specific dose adjustment required for elderly patients; monitor renal function closely due to age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for HEPZATO (HEPZATO).
| Breastfeeding | It is unknown whether melphalan is excreted in human breast milk. However, due to its potential for serious adverse reactions in nursing infants (e.g., myelosuppression, carcinogenesis), breastfeeding is contraindicated during HEPZATO therapy and for at least 1 week after the last dose. No M/P ratio is available. |
| Teratogenic Risk | HEPZATO (melphalan) is contraindicated in pregnant women. It is classified as FDA Pregnancy Category D. First trimester exposure is associated with major congenital malformations including craniofacial defects, skeletal anomalies, and neural tube defects. Second and third trimester exposure may cause intrauterine growth restriction, fetal bone marrow suppression, and neonatal pancytopenia. Risk of fetal loss is increased across all trimesters. |
■ FDA Black Box Warning
Warning: HEPZATO is for use only in patients with unresectable hepatic metastases from ocular melanoma. It should be administered by physicians experienced in hepatic intra-arterial chemotherapy and percutaneous hepatic perfusion (PHP). Serious and life-threatening toxicities include neutropenia, thrombocytopenia, hemorrhage, hypotension, renal impairment, and hepatic sinusoidal obstruction syndrome (SOS).
| Serious Effects |
History of hypersensitivity to melphalan; severe bone marrow suppression; active infection; renal impairment (CrCl < 30 mL/min).
| Precautions | Hepatic sinusoidal obstruction syndrome (SOS); hemorrhage; neutropenia; thrombocytopenia; hypotension; renal impairment; extravasation; carcinogenicity; use in females and males of reproductive potential. |
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| Fetal Monitoring | Monitor complete blood counts weekly during therapy. Assess liver and renal function tests periodically. Perform fetal ultrasound at 4-week intervals to assess growth and anatomy if pregnant. Monitor for signs of maternal infection or bleeding. Cardiac monitoring may be warranted due to risk of arrhythmias. |
| Fertility Effects | Melphalan is known to cause gonadal suppression and infertility in both males and females. In females, it may lead to ovarian failure with amenorrhea, elevated gonadotropins, and irreversible infertility. In males, it may cause azoospermia or oligospermia, which may be permanent. Pre-treatment fertility preservation counseling is recommended. |