Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1648
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LEUKERAN (Tablet)
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dailymed-instance:dosage |
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
0.2mg/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.
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dailymed-instance:descripti... |
LEUKERAN (chlorambucil)
was first synthesized by Everett et al. It is a bifunctional alkylating agent
of the nitrogen mustard type that has been found active against selected human
neoplastic diseases. Chlorambucil is known chemically as 4-[bis(2-chlorethyl)amino]benzenebutanoic
acid and has the following structural formula: Chlorambucil
hydrolyzes in water and has a pKa of 5.8. LEUKERAN
(chlorambucil) is available in tablet form for oral administration. Each film-coated
tablet contains 2 mg chlorambucil and the inactive ingredients colloidal
silicon dioxide, hypromellose, lactose (anhydrous), macrogol/PEG 400, microcrystalline
cellulose, red iron oxide, stearic acid, titanium dioxide, and yellow iron
oxide.
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dailymed-instance:clinicalP... |
Chlorambucil is rapidly
and completely absorbed from the gastrointestinal tract. After single oral
doses of 0.6 to 1.2 mg/kg, peak plasma chlorambucil levels (C)
are reached within 1 hour and the terminal elimination half-life (t)
of the parent drug is estimated at 1.5 hours. Chlorambucil undergoes
rapid metabolism to phenylacetic acid mustard, the major metabolite, and the
combined chlorambucil and phenylacetic acid mustard urinary excretion is extremely
low���less than 1% in 24 hours. In a study of 12 patients
given single oral doses of 0.2 mg/kg of LEUKERAN, the mean dose (12 mg)
adjusted (��SD) plasma chlorambucil Cwas 492��160 ng/mL,
the AUC was 883��329 ng���h/mL, twas
1.3��0.5 hours, and the twas 0.83��0.53 hours.
For the major metabolite, phenylacetic acid mustard, the mean dose (12 mg)
adjusted (��SD) plasma Cwas 306��73 ng/mL,
the AUC was 1204��285 ng���h/mL, the twas
1.8��0.4 hours, and the twas 1.9��0.7 hours. 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. Evidence
of human teratogenicity suggests that the drug crosses the placenta. Chlorambucil
is extensively metabolized in the liver primarily to phenylacetic acid mustard,
which has antineoplastic activity. Chlorambucil and its major metabolite spontaneously
degrade in vivoforming monohydroxy
and dihydroxy derivatives. After a single dose of radiolabeled chlorambucil
(C), approximately 15% 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. In summary, the
pharmacokinetic data suggest that oral chlorambucil undergoes rapid gastrointestinal
absorption and plasma clearance and that it is almost completely metabolized,
having extremely low urinary excretion.
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dailymed-instance:contraind... |
Chlorambucil should not
be used in patients whose disease has demonstrated a prior resistance to the
agent. Patients who have demonstrated hypersensitivity to chlorambucil should
not be given the drug. There may be cross-hypersensitivity (skin rash) between
chlorambucil and other alkylating agents.
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dailymed-instance:supply |
Leukeran is supplied as brown, film-coated, round, biconvex
tablets containing 2 mg chlorambucil in amber glass bottles with child-resistant
closures. One side is engraved with���GX EG3���and the other side
is engraved with an���L.��� Bottle of 50
(NDC 0173-0635-35). Store
in a refrigerator, 2��to 8��C (36��to 46��F).
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dailymed-instance:genericDr... | |
dailymed-instance:boxedWarn... |
WARNING: LEUKERAN (chlorambucil) can severely suppress bone marrow
function. Chlorambucil is a carcinogen in humans. Chlorambucil is probably
mutagenic and teratogenic in humans. Chlorambucil produces human infertility
(see WARNINGS and PRECAUTIONS).
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dailymed-instance:activeMoi... | |
dailymed-instance:inactiveI... |
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:hypromellose,
dailymed-ingredient:lactose_(anhydrous),
dailymed-ingredient:macrogol/PEG_400,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:red_iron_oxide,
dailymed-ingredient:stearic_acid,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:yellow_iron_oxide
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dailymed-instance:precautio... |
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 doseof 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 chlorambucilmay
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.<br/>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.<br/>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 ent to go more than 2 weeks without hematological
and clinical examination during treatment. body weight, temperature, spleen
size, etc., are recorded. It is considered dangerous to allow a pati<br/>Drug Interactions: There are no known drug/drug interactions with chlorambucil.<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section for information on carcinogenesis,
mutagenesis, and impairment of fertility.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category D: See WARNINGS section.<br/>Nursing Mothers: It is not known whether this drug is excreted in human milk.
Because many drugs are excreted in human milk and because of the potential
for serious adverse reactions in nursing infants from chlorambucil, a decision
should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.<br/>Pediatric Use: The safety and effectiveness
in pediatric patients have not been established.<br/>Geriatric Use: Clinical studies of chlorambucil did not include sufficient
numbers of subjects aged 65 and over to determine whether they respond differently
from younger subjects. Other reported clinical experience has not identified
differences in responses between the elderly and younger patients. In general,
dose selection for an elderly patient should be cautious, usually starting
at the low end of the dosing range, reflecting the greater frequency of decreased
hepatic, renal, or cardiac function, and of concomitant disease or other drug
therapy.
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dailymed-instance:overdosag... |
Reversible pancytopenia
was the main finding of inadvertent overdoses of chlorambucil. Neurological
toxicity ranging from agitated behavior and ataxia to multiple grand mal seizures
has also occurred. As there is no known antidote, the blood picture should
be closely monitored and general supportive measures should be instituted,
together with appropriate blood transfusions, if necessary. Chlorambucil is
not dialyzable. Oral LDsingle 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 orallyto rats as a single dose, with recovery. Such a dose
causes bradycardia, excessive salivation, hematuria, convulsions, and respiratory
dysfunction.
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dailymed-instance:genericMe... |
chlorambucil
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dailymed-instance:fullName |
LEUKERAN (Tablet)
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dailymed-instance:adverseRe... |
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.<br/>Gastrointestinal: Gastrointestinal disturbances such as nausea and vomiting,
diarrhea, and oral ulceration occur infrequently.<br/>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).<br/>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).<br/>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).
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dailymed-instance:warning |
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.<br/>Pregnancy: Pregnancy Category D. 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.
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dailymed-instance:indicatio... |
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.
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LEUKERAN
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