LEUKERAN- chlorambucil tablet, film coated

Waylis Therapeutics LLC

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LEUKERAN®
(chlorambucil) Tablets

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).

DESCRIPTION
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.

CLINICAL PHARMACOLOGY

Mechanism of Action
Chlorambucil, an aromatic nitrogen mustard derivative, is an alkylating agent.
Chlorambucil interferes with DNA replication and induces cellular apoptosis via the
accumulation of cytosolic p53 and subsequent activation of Bax, an apoptosis
promoter.

PHARMACOKINETICS
In a study of 12 patients given single oral doses of 0.2 mg/kg of LEUKERAN, the mean
dose-adjusted (±SD) plasma chlorambucil Cmax was 492 ± 160 ng/mL, the AUC was
883 ± 329 ng.h/mL, the mean elimination half-life (t½) was 1.3 ± 0.5 hours, and the
Tmax was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard
(PAAM), the mean dose-adjusted (± SD) plasma Cmax was 306 ± 73 ng/mL, the AUC
was 1204 ± 285 ng.h/mL, mean t½ was 1.8 ± 0.4 hours, and the Tmax was 1.9 ± 0.7
hours.
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 (t½ ) 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 Tmax by 2-fold and reduced the dose-adjusted Cmax 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 (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.

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. It is not curative in any of these disorders but may
produce clinically useful palliation.

CONTRAINDICATIONS
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.
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.

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 on carcinogenesis, mutagenesis, and
impairment of fertility.

Pregnancy
Teratogenic Effects: See WARNINGS section.

Lactation
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.

Pediatric Use
The safety and effectiveness in pediatric patients have not been established.

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.

Use in Patients with Renal Impairment: The impact of renal impairment on

chlorambucil elimination has not been formally studied. The renal elimination of
unchanged chlorambucil and its major active metabolites, phenylacetic acid mustard,
represents less than 1% of the administered dose. In addition, no dose adjustment was
required in 2 dialysis patients on chlorambucil. Therefore, renal impairment is not
expected to significantly impact the elimination of chlorambucil.

Use in Patients with Hepatic Impairment: No formal studies have been conducted
in patients with hepatic impairment. As chlorambucil is primarily metabolized in the liver,
patients with hepatic impairment should be closely monitored for toxicity and dose
reduction may be considered in patients with hepatic impairment when treated with
LEUKERAN (see DOSAGE AND ADMINISTRATION).

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).

OVERDOSAGE
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 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.

DOSAGE AND ADMINISTRATION

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 0.2 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.
1-4
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.

HOW SUPPLIED
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 25 (NDC 80725-610-25)

Store in a refrigerator, 2° to 8°C (36° to 46°F).

REFERENCES
1. NIOSH Alert: Preventing occupational exposures to antineoplastic and other
hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human
Services, Public Health Service, Centers for Disease Control and Prevention, National
Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
2. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational
Exposure to Hazardous Drugs. OSHA, 1999.
http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
3. American Society of Health-System Pharmacists. ASHP guidelines on handling
hazardous drugs. Am J Health-Syst Pharm. (2006) 63:1172-1193.
4. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy
guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology
Nursing Society.

Distributed by: Waylis Therapeutics LLC

Wixom, MI 48393
Made in Germany
Rev. 02/2023

PACKAGE LABEL PRINCIPAL DISPLAY PANEL

Principal Display Panel
NDC 80725-610-25
LEUKERAN®
(chlorambucil) Tablets
2 mg
25 Tablets
Each tablet contains 2 mg chlorambucil.
Rx Only.
Leukeran 2mg 25 ct. Carton

Leukeran 2mg 25 ct. Label

LEUKERAN
chlorambucil tablet, film coated

Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:80725-610

Route of Administration ORAL

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
CHLORAMBUCIL (UNII: 18D0SL7309) (CHLORAMBUCIL - UNII:18D0SL7309) CHLORAMBUCIL 2 mg

Inactive Ingredients
Ingredient Name Strength
SILICON DIOXIDE (UNII: ETJ7Z 6XBU4)
HYPROMELLOSES (UNII: 3NXW29V3WO)
ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
POLYETHYLENE GLYCOL, UNSPECIFIED (UNII: 3WJQ0SDW1A)
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
FERRIC OXIDE RED (UNII: 1K09F3G675)
STEARIC ACID (UNII: 4ELV7Z 65AP)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
FERRIC OXIDE YELLOW (UNII: EX438O2MRT)

Product Characteristics
Color brown Score no s core
Shape ROUND Size 7mm
Flavor Imprint Code GX;EG3;L
Contains

Packaging
Marketing Start Marketing End
# Item Code Package Description
Date Date
NDC:80725-610- 25 in 1 BOTTLE; Type 0: Not a Combination
1 05/15/2023
25 Product

Marketing Information
Marketing Application Number or Monograph Marketing Start Marketing End
Category Citation Date Date
NDA NDA010669 05/15/2023
Labeler - Waylis Therapeutics LLC (117678921)

Revised: 5/2023 Waylis Therapeutics LLC