Chlorambucil
- Chlorambucil is a carcinogen in humans.
- Chlorambucil is probably mutagenic and teratogenic in humans.
- Chlorambucil produces human infertility.

# Dosing Information
- 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 Hodgkins 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.
- There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
- 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 chlorambucil. However, there are insufficient data in patients with hepatic impairment to provide a specific dosing recommendation.
- Convulsions, infertility, leukemia, and secondary malignancies have been observed when chlorambucil was employed in the therapy of malignant and non-malignant diseases.
- There are many reports of acute leukemia arising in patients with both malignant and non-malignant diseases following chlorambucil treatment. In many instances, these patients also received other chemotherapeutic agents or some form of radiation therapy. The quantitation of the risk of chlorambucil-induction of leukemia or carcinoma in humans is not possible. Evaluation of published reports of leukemia developing in patients who have received chlorambucil (and other alkylating agents) suggests that the risk of leukemogenesis increases with both chronicity of treatment and large cumulative doses. However, it has proved impossible to define a cumulative 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.

# PRECAUTIONS
- Many patients develop a slowly progressive lymphopenia during treatment. The lymphocyte count usually rapidly returns to normal levels upon completion of drug therapy. Most patients have some neutropenia after the third week of treatment and this may continue for up to 10 days after the last dose. Subsequently, the neutrophil count usually rapidly returns to normal. Severe neutropenia appears to be related to dosage and usually occurs only in patients who have received a total dosage of 6.5 mg/kg or more in one course of therapy with continuous dosing. About one quarter of all patients receiving the continuous-dose schedule, and one third of those receiving this dosage in 8 weeks or less may be expected to develop severe neutropenia.
- While it is not necessary to discontinue chlorambucil at the first evidence of a fall in neutrophil count, it must be remembered that the fall may continue for 10 days after the last dose, and that as the total dose approaches 6.5 mg/kg, there is a 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.
- Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur infrequently.
- 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.
- 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.
- 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
- Other reported adverse reactions include: pulmonary fibrosis, hepatotoxicity and jaundice, drug fever, peripheral neuropathy, interstitial pneumonia, sterile cystitis, infertility, leukemia, and secondary malignancies.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Chlorambucil in women who are pregnant.
- Patients must be followed carefully to avoid life-endangering damage to the bone marrow during treatment. Weekly examination of the blood should be made to determine hemoglobin levels, total and differential leukocyte counts, and quantitative platelet counts. Also, during the first 3 to 6 weeks of therapy, it is recommended that white blood cell counts be made 3 or 4 days after each of the weekly complete blood counts. Galton et al have suggested that in following patients it is helpful to plot the blood counts on a chart at the same time that body weight, temperature, spleen size, etc., are recorded. It is considered dangerous to allow a patient to go more than 2 weeks without hematological and clinical examination during treatment.
- Oral LD50 single doses in mice are 123 mg/kg. In rats, a single intraperitoneal dose of 12.5 mg/kg of chlorambucil produces typical nitrogen-mustard effects; these include atrophy of the intestinal mucous membrane and lymphoid tissues, severe lymphopenia becoming maximal in 4 days, anemia, and thrombocytopenia. After this dose, the animals begin to recover within 3 days and appear normal in about a week, although the bone marrow may not become completely normal for about 3 weeks. An intraperitoneal dose of 18.5 mg/kg kills about 50% of the rats with development of convulsions. As much as 50 mg/kg has been given orally to rats as a single dose, with recovery. Such a dose causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory dysfunction.
- After single oral doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (Cmax) are reached within 1 hour and the terminal elimination half-life (t12) of the parent drug is estimated at 1.5 hours.
- 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 Tmax by 2-fold and reduced the dose-adjusted Cmax and AUC values by 55% and 20%, respectively.
- 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.
- 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.
- After a single dose of radiolabeled chlorambucil (14C), 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.
Bottle of 50 (NDC 76388-635-50).
NDC 76388-635-50
Chlorambucil
(chlorambucil) Tablets
2 mg
50 Tablets
Each tablet contains 2 mg chlorambucil.
Rx only