ALKERAN - melphalan tablet, film coated
SmithKline Beecham Corporation
ALKERAN®
(melphalan)
Tablets
WARNING
ALKERAN (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. Melphalan is leukemogenic in humans.
Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans.
DESCRIPTION
ALKERAN (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 which is active against selective human neoplastic diseases. It is known chemically as 4-[bis(2-chloroethyl)amino]-L-phenylalanine. The molecular formula is C13H18Cl2N2O2 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.
ALKERAN (melphalan) is available in tablet form for oral administration. Each film-coated tablet contains 2 mg melphalan and the inactive ingredients colloidal silicon dioxide, crospovidone, hypromellose, macrogol/PEG 400, magnesium stearate, microcrystalline cellulose, and titanium dioxide.
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 N7 position of guanine. Like other bifunctional alkylating agents, it is active against both resting and rapidly dividing tumor cells.
Pharmcokinetics
The pharmacokinetics of ALKERAN after oral administration has been extensively studied in adult patients. Plasma melphalan levels are highly variable after oral dosing, both with respect to the time of the first appearance of melphalan in plasma (range approximately 0 to 6 hours) and to the peak plasma concentration (Cmax) (range 70 to 4,000 ng/mL, depending upon the dose) achieved. These results may be due to incomplete intestinal absorption, a variable “first pass” hepatic metabolism, or to rapid hydrolysis. Five patients were studied after both oral and intravenous (IV) dosing with 0.6 mg/kg as a single bolus dose by each route. The areas under the plasma concentration-time curves (AUC) after oral administration averaged 61% ± 26% (± standard deviation [SD]; range 25% to 89%) of those following IV administration. In 18 patients given a single oral dose of 0.6 mg/kg of ALKERAN, the terminal elimination plasma half-life (t1/2) of parent drug was 1.5 ± 0.83 hours. The 24-hour urinary excretion of parent drug in these patients was 10% ± 4.5%, suggesting that renal clearance is not a major route of elimination of parent drug. In a separate study in 18 patients given single oral doses of 0.2 to 0.25 mg/kg of ALKERAN, Cmax and AUC, when dose adjusted to a dose of 14 mg, were (mean ± SD) 212 ± 74 ng/mL and 498 ± 137 ng•hr/mL, respec |
