.  
Chlorambucil

The Elephant Formulary
© 2003-06 Susan K. Mikota DVM and Donald C. Plumb, Pharm.D.
Published by Elephant Care International -
www.elephantcare.org


Elephant specific information, if available, is in blue.

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 assigned to the commercially available tablets.

 

Pharmacology - 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, including lymphocytic leukemia, multiple myeloma, polycythemia vera, macroglobulinemia, and ovarian adenocarcinoma. 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 - In humans, chlorambucil is rapidly and nearly completely absorbed after oral administration. It is highly bound to plasma proteins. While it is not known whether it crosses the blood-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 the liver, primarily to phenylacetic acid mustard, which is active. Phenylacetic acid mustard is further metabolized 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 used with caution in patients with preexisting bone marrow depression or infection, or susceptible to bone marrow depression or infection.

 

Chlorambucil’s teratogenic potential has not been well documented, but it may potentially cause a variety of fetal abnormalities. It is generally recommended to avoid the drug during pregnancy, but because of the seriousness of the diseases treated with chlorambucil, the potential benefits to the mother must be considered. Chlorambucil has been documented to cause irre­versible infertility in male humans, particularly when given during pre-puberty and puberty.

 

Adverse Effects/Warnings - The most commonly associated major adverse effect seen with chlorambucil 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 long term sequelae. Treatment should consist of gut emptying when appropriate (beware of rapidly changing neurologic status if inducing vomiting). Monitoring of CBC’s several times a week for several weeks should be performed after overdoses and blood component therapy may be necessary.

 

Drug Interactions - The principal concern should be the concurrent use with other drugs that are also myelosuppressive, including many of the other antineoplastics and other bone marrow depressant drugs (e.g., chloramphenicol, flucytosine, amphotericin B, or colchicine). Bone marrow 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.

 

Doses -

Horses:

For adjunctive therapy in treating lymphoma using the LAP protocol: Cytosine arabinoside  200 - 300 mg/m2 SubQ or IM once every 1-2 weeks; Chlorambucil 20 mg/m2 PO every 2 weeks (alternating with cytosine arabinoside) and Prednisone 1.1 - 2.2 mg/kg PO every other day. If this protocol is not effective (no response seen in 2-4 weeks) add vincristine at 0.5 mg/m2 IV once a week. Side effects are rare. (Couto 1994)

 

 

Monitoring Parameters - 1) Efficacy; 2) CBC, Platelets once weekly (or once stable every other week) during therapy; 3) Uric acid, liver enzymes; if warranted

 

Client Information - Clients must understand the importance of both administering chlorambucil as directed and to report immediately any signs associated with toxicity (e.g., abnormal bleeding, bruising, urination, depression, infection, shortness of breath, etc.).

 

Dosage Forms/Preparations/FDA Approval Status/Withholding Times -

 

Veterinary-Approved Products: None

 

Human-Approved Products:

Chlorambucil Oral Tablets 2 mg; Leukeran ® (Glaxo Wellcome); (Rx)

 

Disclaimer: the information on this page is used entirely at the reader's discretion,
and is made available on the express condition that no liability, expressed or implied,
 is accepted by the authors or publisher for the accuracy, content, or use thereof.