Veterinary Drug Handbook (VDH) is the reference veterinarians turn to when they want an independent source of information on the drugs that are used in veterinary medicine today.

CHLORAMBUCIL

Chemistry - A nitrogen mustard derivative antineoplastic agent, chlorambucil occurs as an off-white, slightly granular powder. It is very slightly soluble in water.

Storage, Stability, Compatibility

Chlorambucil tablets should be stored in light-resistant, well-closed containers at room temperature. An expiration date of one year after manufacture is assignedto the commercially available tablets.

Pharmacology - CHLORAMBUCIL

Chlorambucil is a cell-cycle nonspecific alkylating antineoplastic/immunosuppressive agent. Its cytotoxic activity stems from cross-linking with cellular DNA.

Uses, Indications

Chlorambucil may be useful in a variety of neoplastic diseases, includinglymphocytic leukemia, multiple myeloma, polycythemia vera, macroglobulinemia, and ovarianadenocarcinoma. It may also be useful as adjunctive therapy for some immune-mediated conditions(e.g., glomerulonephritis, non-erosive arthritis, or immune-mediated skin disease).

Pharmacokinetics - CHLORAMBUCIL

In humans, chlorambucil is rapidly and nearly completely absorbed after oraladministration. It is highly bound to plasma proteins. While it is not known whether it crosses theblood-brain barrier, neurological side effects have been reported. Chlorambucil crosses the placenta, but it is not known whether it enters maternal milk. Chlorambucil is extensively metabolized in theliver, primarily to phenylacetic acid mustard, which is active. Phenylacetic acid mustard is furthermetabolized to other metabolites that are excreted in the urine.

Contraindications, Precautions, Reproductive Safety

Chlorambucil is contraindicated in patients who are hypersensitive to it or have demonstrated resistance to its effects. It should be usedwith caution in patients with preexisting bone marrow depression or infection, or susceptible tobone marrow depression or infection.
Chlorambucil's teratogenic potential has not been well documented, but it may potentially cause avariety of fetal abnormalities. It is generally recommended to avoid the drug during pregnancy, butbecause of the seriousness of the diseases treated with chlorambucil, the potential benefits to themother must be considered. Chlorambucil has been documented to cause irreversible infertility inmale humans, particularly when given during pre-puberty and puberty.

Adverse Effects, Warnings

The most commonly associated major adverse effect seen withchlorambucil therapy is myelosuppression manifested by anemia, leukopenia, and thrombocytopenia. It may occur gradually with nadirs occurring usually within 7-14 days of the start of therapy. Recovery generally takes from 7-14 days. Severe bone marrow depression can result in pancytopenia that may take months to years for recovery. In humans, bronchopulmonary dysplasia with pulmonary fibrosis and uric acid nephropathy, have been reported. These effects are more uncommon and generally associated with chronic, higher dose therapy. Hepatotoxicity has been reported rarely in humans. Alopecia and delayed regrowth of shaven fur have been reported in dogs. Poodles or Kerry blues are more likely to be affected than other breeds.

Overdosage, Acute Toxicity

The oral LD50 in mice is 123 mg/kg. There has been limited experiences with acute overdoses in humans. Doses of up to 5 mg/kg resulted in neurologic (seizures)toxicity and pancytopenia (nadirs at 1-6 weeks post ingestion). All patients recovered without longterm sequelae. Treatment should consist of gut emptying when appropriate (beware of rapidlychanging neurologic status if inducing vomiting). Monitoring of CBC's several times a week forseveral weeks should be performed after overdoses and blood component therapy may benecessary.

Drug Interactions

The principal concern should be the concurrent use with other drugs that arealso myelosuppressive, including many of the other antineoplastics and other bone marrowdepressant drugs (e.g., chloramphenicol, flucytosine, amphotericin B, or colchicine). Bonemarrow depression may be additive. Use with other immunosuppressant drugs (e.g., azathioprine, cyclophosphamide, corticosteroids) may increase the risk of infection.
Laboratory Considerations - Chlorambucil may raise serum uric acid levels. Drugs such as allopurinol may be required to control hyperuricemia in some patients.
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