leukeran

WARNING
LEUKERAN (chlorambucil) can severely suppress bone marrow function leukeran. Chlorambucilis a carcinogen in humans leukeran. Chlorambucil is probably mutagenic and teratogenicin humans leukeran. Chlorambucil produces human infertility (see WARNINGS and PRECAUTIONS) leukeran.

DESCRIPTION
LEUKERAN (chlorambucil) was first synthesized by Everett et al leukeran. It is a bifunctionalalkylating agent of the nitrogen mustard type that has been found active againstselected human neoplastic diseases leukeran. Chlorambucil is known chemically as 4-[bis(2-chlorethyl)amino]benzenebutanoicacid leukeran.

Chlorambucil hydrolyzes in water and has a pKa of 5.8 leukeran.

LEUKERAN (chlorambucil) is available in tablet form for oral administration leukeran. Each film-coated tablet contains 2 mg chlorambucil and the inactive ingredientscolloidal silicon dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400,microcrystalline cellulose, red iron oxide, stearic acid, titanium dioxide,and yellow iron oxide leukeran.

CLINICAL PHARMACOLOGY
Chlorambucil is rapidly and completely absorbed from the gastrointestinal tract leukeran. 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 (t1/2 ) of the parent drug is estimated at 1.5 hours leukeran. Chlorambucil undergoes rapidmetabolism to phenylacetic acid mustard, the major metabolite, and the combinedchlorambucil and phenylacetic acid mustard urinary excretion is extremely low--lessthan 1% in 24 hours leukeran. In a study of 12 patients given single oral doses of 0.2mg/kg of LEUKERAN, the mean dose (12 mg) adjusted (±SD) plasma chlorambucilC max was 492 ± 160 ng/mL, the AUC was 883 ± 329 ng·h/mL,t 1/2 was 1.3 ± 0.5 hours, and the t max was 0.83 ± 0.53 hours leukeran. For the major metabolite, phenylacetic acid mustard, the mean dose (12 mg) adjusted(±SD) plasma C max was 306 ± 73 ng/mL, the AUC was 1204 ±285 ng·h/mL, the t 1/2 was 1.8 ± 0.4 hours, and the t max was1.9 ± 0.7 hours leukeran.

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

Chlorambucil is extensively metabolized in the liver primarily to phenylaceticacid mustard, which has antineoplastic activity leukeran. Chlorambucil and its majormetabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy derivatives leukeran. After a single dose of radiolabeled chlorambucil ( 14 C), approximately 15%to 60% of the radioactivity appears in the urine after 24 hours leukeran. Again, lessthan 1% of the urinary radioactivity is in the form of chlorambucil or phenylaceticacid mustard leukeran. In summary, the pharmacokinetic data suggest that oral chlorambucilundergoes rapid gastrointestinal absorption and plasma clearance and that itis almost completely metabolized, having extremely low urinary excretion leukeran.

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 leukeran. It is not curative in any of these disorders but mayproduce clinically useful palliation leukeran.

CONTRAINDICATIONS
Chlorambucil should not be used in patients whose disease has demonstrated aprior resistance to the agent leukeran. Patients who have demonstrated hypersensitivityto chlorambucil should not be given the drug leukeran. There may be cross-hypersensitivity(skin rash) between chlorambucil and other alkylating agents leukeran.

WARNINGS
Because of its carcinogenic properties, chlorambucil should not be given topatients with conditions other than chronic lymphatic leukemia or malignantlymphomas leukeran. Convulsions, infertility, leukemia, and secondary malignancies havebeen observed when chlorambucil was employed in the therapy of malignant andnon-malignant diseases leukeran.

There are many reports of acute leukemia arising in patients with both malignantand non-malignant diseases following chlorambucil treatment leukeran. In many instances,these patients also received other chemotherapeutic agents or some form of radiationtherapy leukeran. The quantitation of the risk of chlorambucil-induction of leukemiaor carcinoma in humans is not possible leukeran. Evaluation of published reports of leukemiadeveloping in patients who have received chlorambucil (and other alkylatingagents) suggests that the risk of leukemogenesis increases with both chronicityof treatment and large cumulative doses leukeran. However, it has proved impossible todefine a cumulative dose below which there is no risk of the induction of secondarymalignancy leukeran. The potential benefits from chlorambucil therapy must be weighedon an individual basis against the possible risk of the induction of a secondarymalignancy leukeran.

Chlorambucil has been shown to cause chromatid or chromosome damage in humans leukeran. Both reversible and permanent sterility have been observed in both sexes receivingchlorambucil leukeran.

A high incidence of sterility has been documented when chlorambucil is administeredto prepubertal and pubertal males leukeran. Prolonged or permanent azoospermia has alsobeen observed in adult males leukeran. While most reports of gonadal dysfunction secondaryto chlorambucil have related to males, the induction of amenorrhea in femaleswith alkylating agents is well documented and chlorambucil is capable of producingamenorrhea leukeran. Autopsy studies of the ovaries from women with malignant lymphomatreated with combination chemotherapy including chlorambucil have shown varyingdegrees of fibrosis, vasculitis, and depletion of primordial follicles leukeran.

Rare instances of skin rash progressing to erythema multiforme, toxic epidermalnecrolysis, or Stevens-Johnson syndrome have been reported leukeran. Chlorambucil shouldbe discontinued promptly in patients who develop skin reactions leukeran.

Pregnancy: Pregnancy Category D leukeran. Chlorambucil can cause fetal harm when administeredto a pregnant woman leukeran. Unilateral renal agenesis has been observed in 2 offspringwhose mothers received chlorambucil during the first trimester leukeran. Urogenital malformations,including absence of a kidney, were found in fetuses of rats given chlorambucil leukeran. There are no adequate and well-controlled studies in pregnant women leukeran. If thisdrug is used during pregnancy, or if the patient becomes pregnant while takingthis drug, the patient should be apprised of the potential hazard to the fetus leukeran. Women of childbearing potential should be advised to avoid becoming pregnant leukeran.

PRECAUTIONS
General: Many patients develop a slowly progressive lymphopenia during treatment leukeran. The lymphocyte count usually rapidly returns to normal levels upon completionof drug therapy leukeran. Most patients have some neutropenia after the third week oftreatment and this may continue for up to 10 days after the last dose leukeran. Subsequently,the neutrophil count usually rapidly returns to normal leukeran. Severe neutropenia appearsto be related to dosage and usually occurs only in patients who have receiveda total dosage of 6.5 mg/kg or more in one course of therapy with continuousdosing leukeran. 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 expectedto develop severe neutropenia leukeran.

While it is not necessary to discontinue chlorambucil at the first evidenceof a fall in neutrophil count, it must be remembered that the fall may continuefor 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 leukeran. The dose of chlorambucilshould be decreased if leukocyte or platelet counts fall below normal valuesand should be discontinued for more severe depression leukeran.

Chlorambucil should not be given at full dosages before 4 weeks after a fullcourse of radiation therapy or chemotherapy because of the vulnerability ofthe bone marrow to damage under these conditions leukeran. If the pretherapy leukocyteor platelet counts are depressed from bone marrow disease process prior to institutionof therapy, the treatment should be instituted at a reduced dosage leukeran.

Persistently low neutrophil and platelet counts or peripheral lymphocytosissuggest bone marrow infiltration leukeran. If confirmed by bone marrow examination, thedaily dosage of chlorambucil should not exceed 0.1 mg/kg leukeran. Chlorambucil appearsto be relatively free from gastrointestinal side effects or other evidence oftoxicity apart from the bone marrow depressant action leukeran. In humans, single oraldoses of 20 mg or more may produce nausea and vomiting leukeran.

Children with nephrotic syndrome and patients receiving high pulse doses ofchlorambucil may have an increased risk of seizures leukeran. As with any potentiallyepileptogenic drug, caution should be exercised when administering chlorambucilto patients with a history of seizure disorder or head trauma, or who are receivingother potentially epileptogenic drugs leukeran.

Information for Patients: Patients should be informed that the major toxicitiesof chlorambucil are related to hypersensitivity, drug fever, myelosuppression,hepatotoxicity, infertility, seizures, gastrointestinal toxicity, and secondarymalignancies leukeran. Patients should never be allowed to take the drug without medicalsupervision and should consult their physician if they experience skin rash,bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, amenorrhea,or unusual lumps/masses leukeran. Women of childbearing potential should be advised toavoid becoming pregnant leukeran.

Laboratory Tests: Patients must be followed carefully to avoid life-endangeringdamage to the bone marrow during treatment leukeran. Weekly examination of the bloodshould be made to determine hemoglobin levels, total and differential leukocytecounts, and quantitative platelet counts leukeran. Also, during the first 3 to 6 weeksof therapy, it is recommended that white blood cell counts be made 3 or 4 daysafter each of the weekly complete blood counts leukeran. Galton et al have suggestedthat in following patients it is helpful to plot the blood counts on a chartat the same time that body weight, temperature, spleen size, etc., are recorded leukeran. It is considered dangerous to allow a patient to go more than 2 weeks withouthematological and clinical examination during treatment leukeran.

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