Chlorambucil

INDICATIONS AND USAGE LEUKERAN (chlorambucil) is indicated in the treatment of chronic lymphatic (lymphocytic) leukemia, malignant lymphomas including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease. It is not curative in any of these disorders but may produce clinically useful palliation.

DOSAGE AND ADMINISTRATION The usual oral dosage is 0.1 to 0.2 mg/kg body weight daily for 3 to 6 weeks as required. This usually amounts to 4 to 10 mg per day for the average patient. The entire daily dose may be given at one time. These dosages are for initiation of therapy or for short courses of treatment. The dosage must be carefully adjusted according to the response of the patient and must be reduced as soon as there is an abrupt fall in the white blood cell count. Patients with Hodgkin’s disease usually require 0.2 mg/kg daily, whereas patients with other lymphomas or chronic lymphocytic leukemia usually require only 0.1 mg/kg daily. When lymphocytic infiltration of the bone marrow is present, or when the bone marrow is hypoplastic, the daily dose should not exceed 0.1 mg/kg (about 6 mg for the average patient). Alternate schedules for the treatment of chronic lymphocytic leukemia employing intermittent, biweekly, or once-monthly pulse doses of chlorambucil have been reported. Intermittent schedules of chlorambucil begin with an initial single dose of 0.4 mg/kg. Doses are generally increased by 0.1 mg/kg until control of lymphocytosis or toxicity is observed. Subsequent doses are modified to produce mild hematologic toxicity. It is felt that the response rate of chronic lymphocytic leukemia to the biweekly or once-monthly schedule of chlorambucil administration is similar or better to that previously reported with daily administration and that hematologic toxicity was less than or equal to that encountered in studies using daily chlorambucil. Radiation and cytotoxic drugs render the bone marrow more vulnerable to damage, and chlorambucil should be used with particular caution within 4 weeks of a full course of radiation therapy or chemotherapy. However, small doses of palliative radiation over isolated foci remote from the bone marrow will not usually depress the neutrophil and platelet count. In these cases chlorambucil may be given in the customary dosage. It is presently felt that short courses of treatment are safer than continuous maintenance therapy, although both methods have been effective. It must be recognized that continuous therapy may give the appearance of “maintenance” in patients who are actually in remission and have no immediate need for further drug. If maintenance dosage is used, it should not exceed 0.1 mg/kg daily and may well be as low as 0.03 mg/kg daily. A typical maintenance dose is 2 mg to 4 mg daily, or less, depending on the status of the blood counts. It may, therefore, be desirable to withdraw the drug after maximal control has been achieved, since intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment. Procedures for proper handling and disposal of anticancer drugs should be used. Several guidelines on this subject have been published. 1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. SPECIAL POPULATIONS Hepatic Impairment: Patients with hepatic impairment should be closely monitored for toxicity. As chlorambucil is primarily metabolized in the liver, dose reduction may be considered in patients with hepatic impairment when treated with LEUKERAN. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation.

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Waylis Therapeutics LLC Toll-Free at 1-888-514-4727 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Hematologic The most common side effect is bone marrow suppression, anemia, leukopenia, neutropenia, thrombocytopenia, or pancytopenia. 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 Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently. CNS Tremors, muscular twitching, myoclonia, confusion, agitation, ataxia, flaccid paresis, and hallucinations have been reported as rare adverse experiences to chlorambucil which resolve upon discontinuation of drug. Rare, focal and/or generalized seizures have been reported to occur in both children and adults at both therapeutic daily doses and pulse-dosing regimens, and in acute overdose (see PRECAUTIONS: General). Dermatologic Allergic reactions such as urticaria and angioneurotic edema have been reported following initial or subsequent dosing. Skin hypersensitivity (including rare reports of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome) has been reported (see WARNINGS). Miscellaneous Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies (see WARNINGS).

PHARMACOKINETICS In a study of 12 patients given single oral doses of 0.2 mg/kg of LEUKERAN, the mean dose-adjusted (±SD) plasma chlorambucil C max was 492 ± 160 ng/mL, the AUC was 883 ± 329 ng.h/mL, the mean elimination half-life (t½) was 1.3 ± 0.5 hours, and the T max was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard (PAAM), the mean dose-adjusted (± SD) plasma C max was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng.h/mL, mean t½ was 1.8 ± 0.4 hours, and the T max was 1.9 ± 0.7 hours. After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (C max ) are reached within 1 hour and the terminal elimination half-life (t ½ ) of the parent drug is estimated at 1.5 hours. Absorption: Chlorambucil is rapidly and completely (>70%) absorbed from the gastrointestinal tract. Consistent with the rapid, predictable absorption of chlorambucil, the inter-individual variability in the plasma pharmacokinetics of chlorambucil has been shown to be relatively small following oral dosages of between 15 and 70 mg (2-fold intra-patient variability, and a 2 to 4 fold interpatient variability in AUC). The absorption of chlorambucil is reduced when taken after food. In a study of ten patients, food intake increased the median T max by 2-fold and reduced the dose-adjusted C max and AUC values by 55% and 20%, respectively. Distribution: The apparent volume of distribution averaged 0.31 L/kg following a single 0.2 mg/kg oral dose of chlorambucil in 11 cancer patients with chronic lymphocytic leukemia. 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. Metabolism: Chlorambucil is extensively metabolized in the liver primarily to phenylacetic acid mustard, which has antineoplastic activity. Chlorambucil and its major metabolite undergo oxidative degradation to monohydroxy and dihydroxy derivatives. Excretion: After a single dose of radiolabeled chlorambucil ( 14 C), approximately 20% to 60% of the radioactivity appears in the urine after 24 hours. Again, less than 1% of the urinary radioactivity is in the form of chlorambucil or phenylacetic acid mustard.