dose below which there is no risk of the induction of secondary malignancy. the potential benefits from chlorambucil therapy must be weighed on an individual basis against the possible risk of the induction of a secondary malignancy. chlorambucil has been shown to cause chromatid or chromosome damage in humans. both reversible and permanent sterility have been observed in both sexes receiving chlorambucil. a high incidence of sterility has been documented when chlorambucil is administered to prepubertal and pubertal males. prolonged or permanent azoospermia has also been observed in adult males. while most reports of gonadal dysfunction secondary to chlorambucil have related to males, the induction of amenorrhea in females with alkylating agents is well documented and chlorambucil is capable of producing amenorrhea. autopsy studies of the ovaries from women with malignant lymphoma treated with combination chemotherapy including chlorambucil have shown varying degrees of fibrosis, vasculitis, and depletion of primordial follicles. rare instances of skin rash progressing to erythema multiforme, toxic epidermal necrolysis, or stevens-johnson syndrome have been reported. chlorambucil should be discontinued promptly in patients who develop skin reactions. pregnancy chlorambucil can cause fetal harm when administered to a pregnant woman. unilateral renal agenesis has been observed in 2 offspring whose mothers received chlorambucil during the first trimester. urogenital malformations, including absence of a kidney, were found in fetuses of rats given chlorambucil. there are no adequate and well-controlled studies in pregnant women. if this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. women of childbearing potential should be advised to avoid becoming pregnant.

risk of causing irreversible bone marrow damage. the dose of chlorambucil should be decreased if leukocyte or platelet counts fall below normal values and should be discontinued for more severe depression. chlorambucil should not be given at full dosages before 4 weeks after a full course of radiation therapy or chemotherapy because of the vulnerability of the bone marrow to damage under these conditions. if the pretherapy leukocyte or platelet counts are depressed from bone marrow disease process prior to institution of therapy, the treatment should be instituted at a reduced dosage. persistently low neutrophil and platelet counts or peripheral lymphocytosis suggest bone marrow infiltration. if confirmed by bone marrow examination, the daily dosage of chlorambucil should not exceed 0.1 mg/kg. chlorambucil appears to be relatively free from gastrointestinal side effects or other evidence of toxicity apart from the bone marrow depressant action. in humans, single oral doses of 20 mg or more may produce nausea and vomiting. children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil may have an increased risk of seizures. as with any potentially epileptogenic drug, caution should be exercised when administering chlorambucil to patients with a history of seizure disorder or head trauma, or who are receiving other potentially epileptogenic drugs. administration of live vaccines to immunocompromised patients should be avoided.

ed. 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.

ute 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).

) 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.

il 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.