er 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 labelled chlorambucil indicates that the drug is well absorbed after oral dosage.
Metabolism:-
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 bodyweight 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.
5.3 Preclinical safety dat
Mutagenicity and Carcinogenicity:-
As with other cytotoxic agents chlorambucil is mutagenic in in vitro and in vivo genotoxicity tests and carcinogenic in animals and humans.
Effects on fertility:-
In rats, chlorambucil has been shown to damage spermatogenesis and cause testicular atrophy.
Teratogenicity:-
Chlorambucil has been shown to induce developmental abnormalities, such as short or kinky tail, microcephaly and exencephaly, digital abnormalities including ectro-, brachy-, syn- and polydactyly and long-bone abnormalities such as reduction in length, absence of one or more components, total absence of ossification sites in the embryo 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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Core:
Microcrystalline cellulose
Lactose, anhydrous
Colloidal anhydrous silica
Stearic acid
Coat:
Hypromellose
Titanium dioxide
Macrogol/ PEG 400
Synthetic red and yellow iron oxide
6.2 Incompatibilities
Not Applicable.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in a refrigerator at 2°C - 8°C. Store in the original container.
6.5 Nature and contents of container
Leukeran tablets are supplied in amber (Type III) glass bottles with a child resistant polypropylene/ HDPE closure containing 25 or 50 tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handling
Safe handling of Leukeran tablets:-
The handling of Leukeran Tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations (for example, Royal Pharmaceutical Society of Great Britain Working Party on the Handling of Cytotoxic Drugs).
Provided the outer coating of the tablet is intact, there is no risk in handling Leukeran Tablets. Pregnant staff should not handle cytotoxic agents. Leukeran Tablets should not be |
