Leukeran chlorambucil 2 mg Tablet, Film Coated, 25-count — NDC 80725-610-25 (Billing 80725-0610-25)

WARNINGS Because of its carcinogenic properties, chlorambucil should not be given to patients with conditions other than chronic lymphatic leukemia or malignant lymphomas. 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. 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.

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).

Drug Interactions There are no known drug/drug interactions with chlorambucil.

PRECAUTIONS General 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. INFORMATION FOR PATIENTS Patients should be informed that the major toxicities of chlorambucil are related to hypersensitivity, drug fever, myelosuppression, hepatotoxicity, infertility, seizures, gastrointestinal toxicity, and secondary malignancies.

Patients should never be allowed to take the drug without medical supervision and should consult their physician if they experience skin rash, bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, amenorrhea, or unusual lumps/masses. Women of childbearing potential should be advised to avoid becoming pregnant. Laboratory Tests 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. Drug Interactions There are no known drug/drug interactions with chlorambucil. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section for information… [Excerpted — this section continues on DailyMed.]