Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2012 Publisher: Aspen Pharma Trading Limited 12/13 Exchange Place I.F.S.C Dublin 1 Ireland
Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. A probable mode of action involves cross-linkage of the ethylenimonium derivative between 2 strands of helical DNA and subsequent interference with replication.
In a study of 12 patients administered chlorambucil 0.2 mg/kg body weight orally, the mean dose adjusted maximum plasma concentration (492 ± 160 ng/ml) occurred between 0.25 and 2 hours after administration. The mean (± SD) terminal plasma elimination half-life was 1.3 ± 0.5 hours.
After oral administration of [14C]-chlorambucil, maximum plasma radioactivity occurs between 40 and 70 minutes later. Studies have shown that chlorambucil disappears from the plasma with a mean terminal phase life of 1.5 hours and that its urinary excretion is low. A high level of urinary radioactivity after oral or intravenous administration of [14C]-chlorambucil indicates that the drug is well absorbed after oral dosage.
The metabolism of chlorambucil in man appears to be similar to that in laboratory animals and involves S-oxidation of the butyric acid side chain. Bis-2-chlorethyl-2(4-aminophenyl) acetic acid [phenylacetic acid mustard (PAAM)] is a major metabolite of chlorambucil. In a study of 12 patients administered chlorambucil 0.2 mg/kg body weight orally, the mean dose adjusted-peak plasma concentration of PAAM (306 ± 73 ng/ml) was reached within 1 – 3 hours. The mean terminal elimination plasma half-life was 1.8 ± 0.4 hours. The significant contribution of PAAM to the alkylating activity of the drug was evident as the mean area under the plasma concentration time curve (AUC) of PAAM was approximately 1.33 times greater than the AUC of chlorambucil.
As with other cytotoxic agents chlorambucil is mutagenic in in vitro and in vivo genotoxicity tests and carcinogenic in animals and humans.
See information under ‘Pregnancy and Lactation’ section.
Chlorambucil has been shown to induce skeletal abnormalities in the embryos of mice and rats following a single oral administration of 4-20 mg/kg. Chlorambucil has also been shown to induce renal abnormalities in the offspring of rats following a single intraperitoneal injection of 3-6 mg/kg.
Leukeran may cause suppression of ovarian function and amenorrhoea has been reported following Leukeran therapy.
Azoospermia has been observed as a result of therapy with Leukeran although it is estimated that a total dose of at least 400 mg is necessary.
Varying degrees of recovery of spermatogenesis have been reported in patients with lymphoma following treatment with Leukeran in total doses of 400-2600 mg.
In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
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