Overview
DESCRIPTION Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin, is a phenylalanine derivative of nitrogen mustard. Melphalan is a bifunctional alkylating agent that is active against selected human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]- L -phenylalanine.
Mechanism of Action
CLINICAL PHARMACOLOGY Melphalan is an alkylating agent of the bischloroethylamine type. As a result, its cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA, probably by binding at the N 7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells. Pharmacokinetics Following injection, drug plasma concentrations declined rapidly in a biexponential manner with distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, respectively. Estimates of average total body clearance varied among studies, but typical values of approximately 7 to 9 mL/min/kg (250 to 325 mL/min/m 2 ) were observed. One study has reported that on repeat dosing of 0.
Indications
- INDICATIONS AND USAGE Melphalan Hydrochloride for Injection is indicated for the palliative treatment of patients with multiple myeloma for whom oral therapy is not appropriate.
Common Doses
- 16 mg
- 30 mg
- 10 mL
- 0.45 mg
Dosage
DOSAGE AND ADMINISTRATION The usual IV dose is 16 mg/m 2 . Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL) (see PRECAUTIONS, General ). The drug is administered as a single infusion over 15 to 20 minutes. Melphalan is administered at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. Available evidence suggests about one third to one half of the patients with multiple myeloma show a favorable response to the drug.
Black Box Warning
WARNING Melphalan should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Severe bone marrow suppression with resulting infection or bleeding may occur. Controlled trials comparing intravenous (IV) to oral melphalan have shown more myelosuppression with the IV formulation. Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the IV formulation. Melphalan is leukemogenic in humans.
Contraindications
- CONTRAINDICATIONS Melphalan should not be used in patients whose disease has demonstrated prior resistance to this agent. Patients who have demonstrated hypersensitivity to melphalan should not be given the drug.
Side Effects
- ADVERSE REACTIONS (SEE OVERDOSAGE) The following information on adverse reactions is based on data from both oral and IV administration of melphalan as a single agent, using several different dose schedules for treatment of a wide variety of malignancies. Hematologic The most common side effect is bone marrow suppression leading to leukopenia, thrombocytopenia, and anemia. White blood cell count and platelet count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after treatment. Irreversible bone marrow failure has been reported.
Interactions
- Drug Interactions The development of severe renal failure has been reported in patients treated with a single dose of IV melphalan followed by standard oral doses of cyclosporine. Cisplatin may affect melphalan kinetics by inducing renal dysfunction and subsequently altering melphalan clearance. IV melphalan may also reduce the threshold for BCNU lung toxicity. When nalidixic acid and IV melphalan are given simultaneously, the incidence of severe hemorrhagic necrotic enterocolitis has been reported to increase in pediatric patients.