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Chlorambucil

(British Approved Name, rINN)

Drug Nomenclature

International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):

ChlorambucilSynonyms: CB-1348; Chlorambucil; Chlorambucilis; Chlorambucilum; Chloraminophene; Chlorbutinum; Clorambucilo; Klórambucil; Klorambucil; Klorambusiili; NSC-3088; WR-139013
BAN: Chlorambucil
INN: Chlorambucil [rINN (en)]
INN: Clorambucilo [rINN (es)]
INN: Chlorambucil [rINN (fr)]
INN: Chlorambucilum [rINN (la)]
INN: Хлорамбуцил [rINN (ru)]
Chemical name: 4-[4-Bis(2-chloroethyl)aminophenyl]butyric acid
Molecular formula: C14H19Cl2NO2 =304.2
CAS: 305-03-3
ATC code: L01AA02
Read code: y02jJ

Pharmacopoeias. In China, Europe, International, and US.

European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Chlorambucil). A white or almost white, crystalline powder. Practically insoluble in water; freely soluble in alcohol and in acetone. Protect from light.

The United States Pharmacopeia 31, 2008 (Chlorambucil). An off-white, slightly granular powder. M.p. 65° to 69°. Very slightly soluble in water; soluble 1 in 2 of acetone; soluble in dilute alkali. Store in airtight containers. Protect from light.

Storage. The manufacturers recommend that tablets of chlorambucil should be stored at 2° to 8° and kept dry.

Adverse Effects and Treatment

For a general outline see Antineoplastics.

ChlorambucilA reversible progressive lymphocytopenia tends to develop during treatment with chlorambucil. Neutropenia may continue to develop up to 10 days after the last dose. Irreversible bone-marrow depression can occur particularly when the total dosage for the course approaches 6.5 mg/kg.

Other reported adverse effects include gastrointestinal disturbances, hepatotoxicity, skin rashes (rarely Stevens-Johnson syndrome or toxic epidermal necrolysis), peripheral neuropathy, and central neurotoxicity including seizures. Interstitial pneumonia and pulmonary fibrosis have occurred; the latter is usually reversible but fatalities have been recorded. Chlorambucil in high doses may produce azoospermia and amenorrhoea; sterility has developed particularly when chlorambucil has been given to boys at or before puberty. Overdosage may result in pancytopenia and in neurotoxicity, including agitation, ataxia, and grand mal seizures.

Like other alkylating agents, chlorambucil is potentially mutagenic, teratogenic, and carcinogenic, and an increased incidence of acute leukaemias and other secondary malignancies has been reported in patients who have received the drug.

Effects on the bladder

Chlorambucil-induced cystitis was reported in a 73-year-old woman given 2 mg daily for over 2 years for the treatment of lymphocytic lymphoma.

Effects on the eyes

Visual impairment and optic atrophy in a patient who had been receiving chlorambucil for 5 years to control non-Hodgkin’s lymphoma were thought to be due to the drug, although ocular effects are extremely rare with chlorambucil.

Effects on the nervous system

There have been a small number of reports of seizures in patients given chlorambucil. A review of these suggested that in adults, patients with a history of seizures, or those given high doses of chlorambucil may be at increased risk. The reports in children consisted mainly of patients being treated for nephrotic syndrome, possibly because the condition may alter the pharmacokinetics of chlorambucil.

Precautions

For reference to the precautions necessary with antineoplastics. Chlorambucil should be avoided, or given with great care and at reduced doses, for at least 4 weeks after treatment with radiotherapy or other antineoplasties (unless only low doses of radiation have been given to parts remote from the bone marrow and the neutrophil and platelet counts are not depressed). The dose should be reduced if there is lymphocytic involvement of the bone marrow or if it is hypoplastic.

Chlorambucil should be given with care to patients with impaired renal function; consideration should also be given to dose reduction in patients with gross hepatic dysfunction. Children with nephrotic syndrome, patients receiving high-dose pulse therapy with chlorambucil, and those with a history of seizures, may be at increased risk of seizures. Regular blood counts are required during therapy.

Handling and disposal

Chlorambucil is irritant; avoid contact with skin and mucous membranes.

Urine produced for up to 48 hours after a dose of chlorambucil should be handled wearing protective clothing.

Porphyria

Chlorambucil is considered to be unsafe in patients with porphyria because it has been shown to be porphyrinogenic in animals.

Interactions

For a general outline of antineoplastic drug interactions.

Pharmacokinetics

Chlorambucil is rapidly and almost completely absorbed from the gastrointestinal tract after oral doses and is reported to have a terminal half-life in plasma of about 1.5 hours. It is extensively metabolised in the liver, primarily to active phenylacetic acid mustard, which has a slightly longer plasma half-life of about 1.8 to 2.5 hours, and which like chlorambucil also undergoes some spontaneous degradation to further derivatives. Chlorambucil and its metabolites are extensively protein bound. It is excreted in the urine almost entirely as metabolites with less than 1% unchanged.

Uses and Administration

Chlorambucil is an antineoplastic derived from chlormethine and has a similar mode of action. It acts on lymphocytes and to a lesser extent on neutrophils and platelets. Chlorambucil is most valuable in those conditions associated with the proliferation of white blood cells, especially lymphocytes, and is used in the treatment of chronic lymphocytic leukaemia and lymphomas, including Hodgkin’s disease. It is also used in Waldenstrom’s macroglobulinaemia and has been given in gestational trophoblastic tumours.

Although formerly widely used in the management of polycythaemia vera it has largely been superseded. Chlorambucil also has immunosuppressant properties and has been given in autoimmune disorders including amyloidosis, Behcet’s syndrome, glomerular kidney disease, primary biliary cirrhosis, polymyositis, rheumatoid arthritis, and sarcoidosis. The use of chlorambucil in these disorders is discussed further elsewhere, as indicated by the cross-references given below.

Chlorambucil is better tolerated than chlormethine hydrochloride and serious bone-marrow toxicity is not usually a problem with normal doses. When used as a single-agent antineoplastic for chronic lymphocytic leukaemia and lymphomas, chlorambucil is licensed for oral use in usual initial doses of 100 to 200 micrograms/kg daily (usually 4 to 10 mg once daily), for 3 to 8 weeks. A dose of 100 micrograms/kg daily may be adequate for the treatment of non-Hodgkin’s lymphoma; 150 micrograms/kg daily until the total leukocyte count falls below 10 000 cells/mm may be used in chronic lymphocytic leukaemia; and in Hodgkin’s disease, 200 micrograms/kg daily is usually required.

Lower doses may be given as part of a combination regimen. If lymphocytic infiltration of the bone marrow is present or if the bone marrow is hypoplastic, the daily dose should not exceed 100 micrograms/kg. Alternatively, high-dose chlorambucil may be given intermittently. For example, in chronic lymphocytic leukaemia it may be given in an initial single dose of 400 micrograms/kg increased by 100 micrograms/kg at each 2- or 4-week dose interval until control of lymphocytosis is achieved or toxicity occurs. Once a remission has been established the patient may receive continuous maintenance with 30 to 100 micrograms/kg daily. However, short intermittent courses appear to be safer and are generally preferred for maintenance.

In patients with Waldenstrom’s macroglobulinaemia chlorambucil is licensed in an initial oral dose of 6 to 12 mg daily until leucopenia develops. Maintenance therapy with doses of 2 to 8 mg daily may then be given indefinitely.

Total and differential white cell counts and haemoglobin and platelet examinations are recommended each week during treatment with chlorambucil.

Amyloidosis

Chlorambucil may be of use in preserving kidney function and improving survival in patients with amyloidosis secondary to rheumatic disease, the management of which is discussed in more detail on site.

Blood disorders, non-malignant

Chlorambucil may produce a response in cold auto-immune haemolytic anaemia.

Connective tissue and muscular disorders

Chlorambucil has been used as a corticosteroid-sparing agent in patients with Behcet’s syndrome. It has occasionally been tried in polymyositis. In both these conditions, the potential benefits must be weighed against the possibility of toxicity.

Kidney disorders, non-malignant

Chlorambucil has been used in some forms of glomerular kidney disease. In minimal change nephropathy, in which cytotoxics are reserved for the most severe cases because of fears about toxicity, cyclophosphamide is generally preferred to chlorambucil because it is perceived as entailing somewhat less risk; chlorambucil has been used with corticosteroids in patients with membranous nephropathy, but again cyclophosphamide may be better tolerated.

Liver disorders, non-malignant

No treatment has proven unequivocally successful in the management of primary biliary cirrhosis. Chlorambucil is one of a number of drugs for which reports of benefit exist.

Malignant neoplasms

Chlorambucil is used in the management of a number of haematological malignancies including chronic lymphocytic leukaemia, Hodgkin’s disease, indolent low-grade non-Hodgkin’s lymphomas, and Waldenstrom’s macroglobulinaemia. It was formerly used in polycythaemia vera but is now largely superseded.

Ocular disorders, non-malignant

Chlorambucil is one of the immunosuppressants that may be considered for patients with uveitis unresponsive to corticosteroids in tolerable doses.

Pemphigus and pemphigoid

Chlorambucil with prednisone or prednisolone has been reported to be effective in the treatment of pemphigus and pemphigoid.

Rheumatoid arthritis

Chlorambucil has been used for its immunosuppressant properties in a few patients with severe rheumatoid arthritis, especially with vasculitis, who have failed to respond to other drugs. However, the use of cytotoxic immunosuppressants other than methotrexate is considered debatable.

Sarcoidosis

Where drug therapy is required for sarcoidosis, corticosteroids are the usual treatment. Chlorambucil is one of a number of cytotoxic immunosuppressants that have been tried, with variable results, as a second-line therapy.

Preparations

British Pharmacopoeia 2008: Chlorambucil Tablets;

The United States Pharmacopeia 31, 2008: Chlorambucil Tablet.

Proprietary Preparations

Argentina: Leukeran;

Australia: Leukeran;

Austria; Leukeran;

Belgium: Leukeran;

Brazil: Leukeran;

Canada: Leukeran;

Chile: Leukeran;

Czech Republic: Leukeran;

Denmark: Leukeran;

Finland: Leukeran;

Germany; Leukeran;

Greece: Leukeran;

Hong Kong; Leukeran;

India: Leukeran;

Ireland: Leukeran;

Israel: Leukeran;

Italy: Leukeran;

Malaysia: Leukeran;

Mexico: Leukeran;

The Netherlands: Leukeran;

Norway: Leukeran;

New Zealand: Leukeran;

Philippines: Leukeran;

Poland: Leukeran;

Portugal; Leukeran;

Russia: Leukeran;

South Africa: Leukeran;

Singapore: Leukeran;

Spain: Leukeran;

Sweden: Leukeran;

Switzerland: Leukeran;

Thailand: Leukeran;

Turkey: Leukeran;

United Kingdom (UK): Leukeran.

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