Chlorambucil

Hodgkin's disease, certain forms of non-Hodgkin's lymphoma, chronic lymphocytic leukaemia, Waldenstrom's macroglobulinaemia.

Chlorambucil produces its anti-cancer effects by interfering with DNA replication and damaging the DNA in a cell. The DNA damage induces cell cycle arrest and cellular apoptosis via the accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis promoter.

Chlorambucil alkylates and cross-links DNA during all phases of the cell cycle, inducing DNA damage via three different methods of covalent adduct generation with double-helical DNA:

• Attachment of alkyl groups to DNA bases, resulting in the DNA being fragmented by repair enzymes in their attempts to replace the alkylated bases, preventing DNA synthesis and RNA transcription from the affected DNA.
• DNA damage via the formation of cross-links which prevents DNA from being separated for synthesis or transcription.
• Induction of mispairing of the nucleotides leading to mutations.

The precise mechanisms by which Chlorambucil acts to kill tumor cells are not yet completely understood.

Hodgkin's disease: 200 mcg/kg/day for 4-8 wk.

Non-Hodgkin's lymphoma: 100-200 mcg/kg/day for 4-8 wk. Maintenance: Reduced daily dosage of intermittent courses of treatment.

Chronic lymphocytic leukaemia: Initially, 150 mcg/kg/day until the total leukocyte count falls to 10,000 microliter. Treatment may be resumed 4 wk after at a dose of 100 mcg/kg/day.

Waldenstrom's macroglobulinaemia: Starting dose of 6-12 mg daily until leucopenia occurs followed by 2-8 mg daily.

Administration

Should be taken on an empty stomach: Ensure adequate hydration. Swallow whole, do not chew/crush.

Pregnancy (1st trimester) & lactation.

Bone marrow suppression, seizures in childn with nephrotic syndrome, nausea, vomiting, diarrhoea, oral ulceration. Rarely, irreversible bone marrow failure, allergic reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, seizures, movement disorders, interstitial pulmonary fibrosis, interstitial pneumonia, hepatotoxicity, jaundice, sterile cystitis, drug fever

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Monitor FBC closely. Bone marrow suppression reversible only if withdrawn early enough. Should not be given to patients who have recently undergone radio- or chemotherapy. In lymphocytic infiltration of bone marrow or hypoplastic bone marrow, max daily dose is 0.1 mg/kg. Childn with nephrotic syndrome, patients on high pulse dosing regimens, history of seizure disorders. Renal or hepatic impairment. Ensure adequate contraceptive precautions. Pregnancy.

Cytotoxic Chemotherapy