WARNING
LEUKERAN (chlorambucil) can severely suppress bone marrow function. Chlorambucil is a carcinogen in humans. Chlorambucil is probably mutagenic and teratogenic in humans. Chlorambucil produces human infertility (see WARNINGS and PRECAUTIONS).
DESCRIPTION
LEUKERAN (chlorambucil) was first synthesized by Everett et al. It is a bifunctional alkylating agent of the nitrogen mustard type that has been found active against selected human neoplastic diseases. Chlorambucil is known chemically as 4-[bis(2-chlorethyl)amino]benzenebutanoic acid and has the following structural formula:
Chlorambucil hydrolyzes in water and has a pKa of 5.8.
LEUKERAN (chlorambucil) is available in tablet form for oral administration. Each film-coated tablet contains 2mg chlorambucil and the inactive ingredients colloidal silicon dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400, microcrystalline cellulose, red iron oxide, stearic acid, titanium dioxide, and yellow iron oxide.
CLINICAL PHARMACOLOGY
Chlorambucil is rapidly and completely absorbed from the gastrointestinal tract. After single oral doses of 0.6 to 1.2mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1hour and the terminal elimination half-life (t½) of the parent drug is estimated at 1.5hours. Chlorambucil undergoes rapid metabolism to phenylacetic acid mustard, the major metabolite, and the combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely low — less than 1% in 24hours. In a study of 12patients given single oral doses of 0.2mg/kg of LEUKERAN, the mean dose (12mg) adjusted (± SD) plasma chlorambucil Cmax was 492±160ng/mL, the AUC was 883±329ng•h/mL, t½ was 1.3±0.5hours, and the tmax was 0.83±0.53hours. For the major metabolite, phenylacetic acid mustard, the mean dose (12mg) adjusted (± SD) plasma Cmax was 306±73ng/mL, the AUC was 1204±285ng•h/mL, the t½ was 1.8±0.4hours, and the tmax was 1.9±0.7hours.
Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined. Evidence of human teratogenicity suggests that the drug crosses the placenta.
Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy derivatives. After a single dose of radiolabeled chlorambucil (14C), approximately 15% to 60% of the radioactivity appears in the urine after 24hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard. In summary, the pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.
INDICATIONS AND USAGE
LEUKERAN (chlorambucil) is indicated in the treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease. It is not curative in any of these disorders but may produce clinically useful palliation.
CONTRAINDICATIONS
