Meitheal Pharmaceuticals Inc.
(For Intravenous Infusion)
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 to oral melphalan have shown more myelosuppression with the intravenous formulation. Hypersensitivity reactions, including anaphylaxis, have occurred in approximately 2% of patients who received the intravenous formulation. Melphalan is leukemogenic in humans. Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.
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. The molecular formula is C13 H18 Cl2 N2 O2 and the molecular weight is 305.20. The structural formula is:
Melphalan is the active L-isomer of the compound and was first synthesized in 1953 by Bergel and Stock; the D-isomer, known as medphalan, is less active against certain animal tumors, and the dose needed to produce effects on chromosomes is larger than that required with the L-isomer. The racemic (DL-) form is known as merphalan or sarcolysin.
Melphalan is practically insoluble in water and has a pKa1 of ~2.5.
Melphalan hydrochloride for injection is supplied as a sterile, nonpyrogenic, freeze-dried powder. Each single-dose vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone. Melphalan hydrochloride for injection is reconstituted using the sterile diluent provided. Each vial of sterile diluent contains sodium citrate 0.2 g, propylene glycol 6 mL, ethanol (96%) 0.52 mL, and water for injection to a total of 10 mL. Melphalan hydrochloride for injection is administered intravenously.
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 N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
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/m2) were observed. One study has reported that on repeat dosing of 0.5 mg/kg every 6 weeks, the clearance of melphalan decreased from 8.1 mL/min/kg after the first course, to 5.5 mL/min/kg after the third course, but did not decrease appreciably after the third course. Mean (±SD) peak melphalan plasma concentrations in myeloma patients given intravenous melphalan at doses of 10 or 20 mg/m2 were 1.2 ± 0.4 and 2.8 ± 1.9 mcg/mL, respectively.
The steady-state volume of distribution of melphalan is 0.5 L/kg. Penetration into cerebrospinal fluid (CSF) is low. The average melphalan binding to plasma proteins is highly variable (range: 53% to 92%). Serum albumin is the major binding protein, accounting for approximately 40% to 60% of the plasma protein binding, while α1 -acid glycoprotein accounts for about 20% of the plasma protein binding. Approximately 30% of melphalan is (covalently) irreversibly bound to plasma proteins. Interactions with immunoglobulins have been found to be negligible.
Melphalan is eliminated from plasma primarily by chemical hydrolysis to monohydroxymelphalan and dihydroxymelphalan. Aside from these hydrolysis products, no other melphalan metabolites have been observed in humans. Although the contribution of renal elimination to melphalan clearance appears to be low, one study noted an increase in the occurrence of severe leukopenia in patients with elevated BUN after 10 weeks of therapy.
A randomized trial compared prednisone plus intravenous melphalan to prednisone plus oral melphalan in the treatment of myeloma. As discussed below, overall response rates at week 22 were comparable; however, because of changes in trial design, conclusions as to the relative activity of the 2 formulations after week 22 are impossible to make.
Both arms received oral prednisone starting at 0.8 mg/kg/day with doses tapered over 6 weeks. Melphalan doses in each arm were:
Arm 1: Oral melphalan 0.15 mg/kg/day x 7 followed by 0.05 mg/kg/day when WBC began to rise.
Arm 2: Intravenous melphalan 16 mg/m2 q 2 weeks x 4 (over 6 weeks) followed by the same dose every 4 weeks.
Doses of melphalan were adjusted according to the following criteria:
|WBC/mm3||Platelets||Percent of Full Dose|
One hundred seven patients were randomized to the oral melphalan arm and 203 patients to the intravenous melphalan arm. More patients had a poor-risk classification (58% versus 44%) and high tumor load (51% versus 34%) on the oral compared to the intravenous arm (P <0.04). Response rates at week 22 are shown in the following table:
|Oral melphalan||100||44 (44%)||P> 0.2|
|Intravenous melphalan||195||74 (38%)|
Because of changes in protocol design after week 22, other efficacy parameters such as response duration and survival cannot be compared.
Severe myelotoxicity (WBC ≤1,000 and/or platelets ≤25,000) was more common in the intravenous melphalan arm (28%) than in the oral melphalan arm (11%).
An association was noted between poor renal function and myelosuppression; consequently, an amendment to the protocol required a 50% reduction in intravenous melphalan dose if the BUN was ≥30 mg/dL. The rate of severe leukopenia in the intravenous arm in the patients with BUN over 30 mg/dL decreased from 50% (8/16) before protocol amendment to 11% (3/28) (P = 0.01) after the amendment.
Before the dosing amendment, there was a 10% (8/77) incidence of drug-related death in the intravenous arm. After the dosing amendment, this incidence was 3% (3/108). This compares to an overall 1% (1/100) incidence of drug-related death in the oral arm.
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