Leukeran (Chlorambucil)


Glaxo Wellcome


Antineoplastic Agent

Action And Clinical Pharmacology: Chlorambucil is an aromatic nitrogen mustard derivative which acts as a bifunctional alkylating agent. Alkylation takes place through the formation of a highly reactive ethylenimonium radical. A probable mode of action involves cross-linkage of the ethylenimonium derivative between two strands of helical DNA and subsequent interference with replication.

After oral administration of carbon-14 labelled 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 half-life of 1.5 hours and that its urinary excretion is low. A high level of urinary radioactivity after oral or i.v. administration of carbon-14 labelled chlorambucil indicates that the drug is well absorbed after oral dosage.

Chlorambucil and its metabolites are extensively bound to plasma and tissue proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically albumin. Cerebrospinal fluid levels of chlorambucil have not been determined. Evidence of human teratogenicity suggests that the drug crosses the placenta.

Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard which has antineoplastic activity. The peak plasma levels of chlorambucil and phenylacetic acid mustard are similar, approximating 1 µg/mL; however, the metabolite’s half-life is 1.6 times greater than that of the parent drug. Chlorambucil and its major metabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy derivatives. After a single dose of radiolabelled chlorambucil (carbon-14), approximately 15 to 60% of the radioactivity appears in the urine after 24 hours. Less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard. In summary, the pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal absorption and plasma clearance and that it is almost completely metabolized, having extremely low urinary excretion.

Indications And Clinical Uses: Treatment of chronic lymphocytic leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma and Hodgkin’s disease. It is not curative but produces remissions, some of which may be striking in a substantial portion of patients.

Contra-Indications: Should not be administered to patients who are resistant to the drug or who have developed hypersensitivity to it. There may be cross-hypersensitivity (skin rash) between chlorambucil and other alkylating agents.

Chlorambucil should not be used within 4 weeks of a full course of radiation or chemotherapy.

Manufacturers’ Warnings In Clinical States: Caution: Chlorambucil is a potent drug product and should be used only by physicians experienced with cancer chemotherapeutic drugs. Blood counts should be taken once or twice weekly. Discontinue or reduce the dosage upon evidence of abnormal depression of the bone marrow (see Contraindications and Precautions).

Chlorambucil, a derivative of nitrogen mustard, is a potent drug. It is for use only under the direction of physicians experienced in the administration of cancer chemotherapeutic drugs.

Rare instances of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson’s syndrome have been reported. Chlorambucil should be discontinued promptly in patients who develop skin reactions.

Pregnancy: When cytotoxic drugs are used in pregnancy, the possible teratogenic effect on the fetus should be kept in mind. It is therefore advisable to delay treatment with these drugs as long as possible and certainly until after the first three months of pregnancy.

Lactation: Mothers receiving chlorambucil should not breast-feed.

Precautions: Since chlorambucil is capable of producing irreversible bone marrow depression, blood counts should be monitored once or twice weekly in patients under treatment.

At therapeutic dosage, chlorambucil depresses lymphocytes and has less effect on neutrophil and platelet counts and on hemoglobin levels. Discontinuation of chlorambucil is not necessary at the first sign of a fall in neutrophils but it must be remembered that the fall may continue for 10 days or more after the last dose.

When lymphocytic infiltration of the bone marrow is present, or the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg body weight.

Patients with evidence of impaired renal function should be carefully monitored as they are prone to additional myelosuppression associated with azotemia.

Development of acute leukemia after chlorambucil therapy for chronic lymphocytic leukemia has been reported. However it was not clear whether the acute leukemia was part of the natural history of the disease or if the chemotherapy was the cause.

A comparison of patients with ovarian cancer who received alkylating agents with those who did not, showed that the use of alkylating agents including chlorambucil, significantly increased the incidence of acute leukemia.

Acute myelogenous leukemia has been reported in a small proportion of patients receiving chlorambucil as long-term adjuvant therapy for breast cancer.

The leukemogenic risk must be balanced against the potential therapeutic benefit when considering the use of chlorambucil.

Children with nephrotic syndrome may have an increased risk of seizures if administered concurrent chlorambucil. As with any potentially epileptogenic drug, caution should be exercised when administering chlorambucil to patients with a history of seizure disorder, head trauma, or receiving other potentially epileptogenic drugs.

Drug Interactions: Animal studies indicate that patients who receive phenylbutazone may require a reduction of the standard chlorambucil doses because of the possibility of enhanced chlorambucil toxicity.

Patients with Impaired Hepatic Function: Consideration should be given to dose reduction in patients with gross hepatic dysfunction.

Impairment of Fertility, Teratogenic Effects, Mutagenesis: Chlorambucil may cause suppression of ovarian function. Amenorrhea has been reported following chlorambucil therapy.

Azoospermia has been observed as a result of therapy with chlorambucil although it is estimated that a total dose of at least 400 mg is necessary.

Varying degrees of recovery of spermatogenesis have been reported in patients with lymphoma following treatment with chlorambucil in total doses of 410 to 2 600 mg.

As with other cytotoxic agents chlorambucil is potentially teratogenic.

As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving chlorambucil.

Chlorambucil has been shown to cause chromatid or chromosome damage in man.

Children: The safety and effectiveness in children have not been established.

Adverse Reactions: The most common side effect is bone marrow suppression. Although bone marrow suppression frequently occurs, it is usually reversible if the chlorambucil is withdrawn early enough. However, irreversible bone marrow failure has been reported.

Gastrointestinal disturbances such as nausea and vomiting, diarrhea and oral ulceration occur infrequently. Other side effects may be encountered but usually only when the therapeutic dosage has been exceeded.

Severe interstitial pulmonary fibrosis has occasionally been reported in patients with chronic lymphocytic leukemia on long-term chlorambucil therapy. Pulmonary fibrosis may be reversible on withdrawal of chlorambucil.

Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) has been reported (see Warnings).

Other reported adverse reactions include hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies (see Precautions).

Seizures have occurred in children with nephrotic syndrome treated with chlorambucil and dose related focal fits in adults have been reported (see Precautions).

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Reversible pancytopenia was the main finding of inadvertent overdose of chlorambucil. Neurological toxicity ranging from agitated behavior and ataxia to multiple grand mal seizures has also occurred. As there is no known antidote, the blood picture should be closely monitored and general supportive measures should be instituted together with appropriate blood transfusion if necessary. Chlorambucil is not diazylable.

Dosage And Administration: Chronic Lymphocytic Leukemia: Treatment with chlorambucil is usually started after the patient has developed symptoms or when there is evidence of impaired bone marrow function (but not marrow failure) as indicated by the peripheral blood count.

Initially, chlorambucil is given at the dose of 0.15 mg/kg/day until the total leukocyte count is formed to 10 000/L. Treatment may be resumed 4 weeks after the end of the first course and continued at a dosage of 0.1 mg/kg/day.

In a proportion of patients, usually after about 2 years of treatment, the blood leukocyte count is reduced to the normal range, enlarged spleen and lymph nodes become impalpable and the proportion of lymphocytes in the bone marrow is reduced to less than 20%.

Patients with evidence of bone marrow failure should first be treated with prednisolone and evidence of marrow regeneration should be obtained before commencing treatment with chlorambucil.

Non-Hodgkin’s Lymphoma: Used as a single agent, the usual dosage is 0.1 to 0.2 mg/kg/day for 4 to 8 weeks initially. Maintenance therapy is then given either by a reduced daily dosage or intermittent courses of treatment.

Chlorambucil is useful in the management of patients with advanced lymphocytic lymphoma and those who have relapsed after radiotherapy.

There is no significant difference in the overall response rate obtained with chlorambucil as a single agent and combination chemotherapy in patients with advanced non-Hodgkin’s lymphocytic lymphoma.

Hodgkin’s Disease: Used as a single agent, a typical dosage is 0.2 mg/kg/day for 4 to 8 weeks. Chlorambucil is usually included in combination therapy and a number of regimes have been used. Chlorambucil may also be used as an alternative to nitrogen mustard with a reduction in toxicity but similar therapy results.

Special Instructions: Tablets should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging those materials for transport.

All materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1 000°C or more. Sealed containers may explode.

Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.

Provided the outer coating is intact, there is no risk to handling. Chlorambucil tablets should not be divided.

Availability And Storage: Each white ellipsoid, sugar-coated tablet, imprinted (with edible black ink) with “635” on one side, contains: chlorambucil 2 mg. Nonmedicinal ingredients: confectioner’s sugar, lactose, magnesium stearate and pregelatinized cornstarch; tablet coating: carnauba wax (No. 1 Yellow), liquid sucrose, pharmaceutical glaze, polysorbate 60, powdered acacia and wheat starch. Bottles of 25. Store at a temperature between 15 and 25°C in a dry place. (Shown in Product Recognition Section)

LEUKERAN® Glaxo Wellcome Chlorambucil Antineoplastic Agent

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