chlorambucil
DESCRIPTION:
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).
LEUKERAN (chlorambucil) was first synthesized by Everett et al. (REF. 1) 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.
Chlorambucil hydrolyzes in water and has a pKa of 5.8.
LEUKERAN (chlorambucil) is available in tablet form for oral administration.
Each sugar-coated tablet contains 2 mg chlorambucil and the inactive ingredients
acacia, corn and wheat starch, lactose, magnesium stearate, pharmaceutical
glaze, polysorbate 60, sucrose, and talc. Printed with edible black ink.
ACTIONS/CLINICAL PHARMACOLOGY:
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 are
reached within 1 hour and the terminal half-life 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. The
peak plasma levels of chlorambucil and phenylacetic acid mustard are similar,
approximating 1 mcgm/mL; however, the metabolite's half-life is 1.6 times
greater than the parent drug. (REF. 2,3)
Chlorambucil and its metabolites are extensively bound to plasma and tissue
proteins. In vitro, chlorambucil is 99% bound to plasma proteins, specifically
albumin. (REF. 4) Cerebrospinal fluid levels of chlorambucil have not been
determined. Evidence of human teratogenicity suggests that the drug crosses the
placenta. (REF. 5,6)
Chlorambucil is extensively metabolized in the liver primarily to phenylacetic
acid mustard which has antineoplastic activity. (REF. 2,3) Chlorambucil and its
major metabolite spontaneously degrade in vivo forming monohydroxy and dihydroxy
derivatives. (REF. 2) After a single dose of radiolabeled chlorambucil (14C),
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. (REF. 2) 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.
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. (REF. 7-9) There may be cross-
hypersensitivity (skin rash) between chlorambucil and other alkylating agents.
(REF. 10)
WARNINGS:
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.
Because of its carcinogenic properties, chlorambucil should not be given to
patients with conditions other than chronic lymphatic leukemia or malignant
lymphomas. Convulsions, (REF. 11) infertility, (REF. 12) leukemia (REF. 13,14)
and secondary malignancies (REF. 15) 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
(REF. 16) and non-malignant (REF. 17) 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 man.
(REF. 18,19) 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. (REF. 20) Prolonged or permanent
azoospermia has also been observed in adult males. (REF. 21) 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. (REF. 22,23)
Rare instances of skin rash, progressing to erythema multiforme, toxic epidermal
necrolysis, or Stevens-Johnson syndrome have been reported. (REF. 8-9)
Chlorambucil should be discontinued promptly in patients who develop skin
reactions.
PREGNANCY: Pregnancy Category D: Chlorambucil can cause fetal harm when
administered to a pregnant woman. Unilateral renal agenesis has been observed in
two offspring whose mothers received chlorambucil during the first trimester.
(REF. 5,6) Urogenital malformations, including absence of a kidney, were found
in fetuses of rats given chlorambucil. (REF. 24) 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. (REF. 25)
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 (REF. 11) and patients receiving high pulse
doses of chlorambucil (REF. 26) 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, head
trauma, or receiving other potentially epileptogenic drugs.
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 (REF. 25) 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: Pregnancy Category D: See WARNINGS section.
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.
PEDIATRIC USE: The safety and effectiveness in pediatric patients have not been
established.
DRUG INTERACTIONS:
There are no known drug/drug interactions with chlorambucil.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
HEMATOLOGIC: The most common side effect is bone marrow suppression. (REF. 27)
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. (REF. 28,29)
GASTROINTESTINAL: Gastrointestinal disturbances such as nausea and vomiting,
diarrhea, and oral ulceration occur infrequently.
CNS: Tremors, muscular twitching, 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 (REF.
11,30,31) and adults (REF. 26,32-35) at both therapeutic daily doses, pulse
dosing regimens, and in acute overdose (see PRECAUTIONS: General).
DERMATOLOGIC: Skin hypersensitivity (including rare reports of skin rash
progressing to erythema multiforme, (REF. 9) toxic epidermal necrolysis, (REF.
8) 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. (REF. 36,37) Neurological toxicity ranging from agitated behavior
and ataxia to multiple grand mal seizures has also occurred. (REF. 30,36) 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 a 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. (REF. 38,39) 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 2mg 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
considered. Several guidelines on this subject have been published. (REF. 40-46)
There is no general agreement that all of the procedures recommended in the
guidelines are necessary or appropriate.
REFERENCES:
1. Everett JL, Roberts JJ, Ross WCJ. Aryl- 2-halogenoalkylamines: Pt. XII. Some
carboxylic derivatives of NN-Di-2-chloroethylaniline. J Chem Soc. 1953: 3:2386-
2392.
2. Alberts DS, Chang SY, Chen H-SG, Larcom BJ, Jones SE. Pharmacokinetics and
metabolism of chlorambucil in man. Cancer Treat Rev. 1979;6(suppl):9-17.
3. McLean A, Woods RL, Catovsky D, Farmer P. Pharmacokinetics and metabolism of
chlorambucil in patients with malignant disease. Cancer Treat Rev.
1979;6(suppl):33-42.
4. Ehrsson H, Lonroth U, Wallin I, Ehrnebo M, Nilsson SO. Degradation of
chlorambucil in aqueous solution: Influence of human albumin binding. J Pharm
Pharmacol. 1981;33:313-315. Communications.
5. Shotton D, Monie IW. Possible teratogenic effect of chlorambucil on a human
fetus. JAMA. 1963;186:74-75.
6. Steege JF, Caldwell DS. Renal agenesis after first trimester exposure to
chlorambucil. South Med J. 1980;73:1414-1415.
7. Knisley RE, Settipane GA, Albala MM. Unusual reaction to chlorambucil in a
patient with chronic lymphocytic leukemia. Arch Dermatol. 1971;104:77-79.
8. Pietrantonio F, Moriconi L, Torino F, Romano A, Gangovich A. Unusual reaction
to chlorambucil: a case report. Cancer Lett. 1990;54:109-111.
9. Hitchins RN, Hocker GA, Thompson DB. Chlorambucil allergy--a series of three
cases. Aust NZ J Med. 1987;17:600-602.
10. Weiss RB, Bruno S. Hypersensitivity reactions to cancer chemotherapeutic
agents. Ann Intern Med. 1981;94:66-72.
11. Williams SA, Makker SP, Grupe WE. Seizures: A significant side effect of
chlorambucil therapy in children. J Pediatr. 1978;93:516-518.
12. Freckman HA, Fry HL, Mendez FL, Maurer ER. Chlorambucil-prednisolone therapy
for disseminated breast carcinoma. JAMA. 1964;189:23-26.
13. Aymard JP, Frustin J, Witz F, Colomb JN, Lederlin P, Herbeuval R. Acute
leukemia after prolonged chlorambucil treatment for non- malignant disease: a
report of a new case and literature survey. Acta Haematol (Basel). 1980;63:283-
285.
14. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute
leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J
Med. 1981;304:441-447.
15. Lerner HJ. Acute myelogenous leukemia in patients receiving chlorambucil as
long-term adjuvant chemotherapy for stage II breast cancer. Cancer Treat Rep.
1978;62:1135-1138.
16. Zarrabi MH, Grunwald HW, Rosner F. Chronic lymphocytic leukemia terminating
in acute leukemia. Arch Intern Med. 1977;137:1059-1064.
17. Cameron S. Chlorambucil and leukemia. N Eng J Med. 1977;296:1065.
18. Lawler SD, Lele KP. Chromosomal damage induced by chlorambucil in chronic
lymphocytic leukemia. Scand J Haematol. 1972;9:603-612.
19. Stevenson AC, Patel C. Effects of chlorambucil on human chromosomes. Mutat
Res. 1973;18:333-351.
20. Guesry P, Lenoir G, Broyer M. Gonadal effects of chlorambucil given to
prepubertal and pubertal boys for nephrotic syndrome. J Pediatr. 1978;92: 299-
303.
21. Richter P, Calamera JC, Morgenfeld MC, Kierszenbaum AL, Lavieri JC, Mancini
RE. Effect of chlorambucil on spermatogenesis in the human with malignant
lymphoma. Cancer. 1970;25:1026-1030.
22. Morgenfeld MC, Goldberg V, Parisier H, Bugnard SC, Bur GE. Ovarian lesions
due to cytostatic agents during the treatment of Hodgkin's disease. Surg Gynecol
Obstet. 1972;134:826-828.
23. Sobrinho LG, Levine RA, DeConti RC. Amenorrhea in patients with Hodgkin's
disease treated with antineoplastic agents. Am J Obstet Gynecol. 1971;109: 135-
139.
24. Monie IW. Chlorambucil-induced abnormalities of the urogenital system of rat
fetuses. Anat Rec. 1961;139:145-153.
25. Galton DAG, Israels LG, Nabarro JDN, Till M. Clinical trials of p-(DI- 2-
chloroethylamino)-phenylbutyric acid (CB 1348) in malignant lymphoma. Br Med J.
1955;2:1172-1176.
26. Ciobanu N, Runowicz C, Gucalp R, et al. Reversible central nervous system
toxicity associated with high-dose chlorambucil in autologous bone marrow
transplantation for ovarian carcinoma. Cancer Treat Rep. 1987;71:1324-1325.
27. Moore GE, Bross ID, Ausman R, et al. Effects of chlorambucil (NSC-3088) in
374 patients with advanced cancer. Eastern Clinical Drug Evaluation Program.
Cancer Chemother Rep. 1968;52(pt 1):661-666.
28. Galton DA, Wiltshaw E, Szur L, Dacie JV. The use of chlorambucil and
steroids in the treatment of chronic lymphocytic leukemia. Br J Haematol.
1961;7:73-98.
29. Rudd P, Fries JF, Epstein WV. Irreversible bone marrow failure with
chlorambucil. J Rheumatol. 1975;2:421-429.
30. Wolfson S, Olney MB. Accidental ingestion of a toxic dose of chlorambucil:
report of a case in a child. JAMA. 1957;165:239-240.
31. Byrne TN, Moseley TAE, Finer MA. Myoclonic seizures following chlorambucil
overdose. Ann Neurol. 1981;9:191-194.
32. LaDelfa I, Bayer N, Myers R, Hoffstein V. Chlorambucil-induced myoclonic
seizures in an adult. J Clin Oncol. 1985;3:1691-1692.
33. Naysmith A, Robson RH. Focal fits during chlorambucil therapy. Postgrad Med
J. 1979;55:806-807.
34. Blank DW, Nanji AA, Schreiber DH, Hudman C, Sanders HD. Acute renal failure
and seizures associated with chlorambucil overdose. J Toxicol Clin Toxicol.
1983;20:361-365.
35. Ammenti A, Reitter B, Muller-Wiefel DE. Chlorambucil neurotoxicity: report
of two cases. Helv Paediatr Acta. 1980;35:281-287.
36. Green AA, Naiman JL. Chlorambucil poisoning. Am J Dis Child. 1968;116: 190-
191.
37. Enck RE, Bennett JM. Inadvertent chlorambucil overdose in adults. NY State J
Med. 1977;77:1480-1481.
38. Knospe WH, Loeb V Jr, Huguley CM. Bi-weekly chlorambucil treatment of
chronic lymphocytic leukemia. Cancer. 1974;33:555-562.
39. Sawitsky A, Rai KR, Glidewell O, et al. Comparison of daily versus
intermittent chlorambucil and prednisone therapy in the treatment of patients
with chronic lymphocytic leukemia. Blood. 1977;50:1049-1059.
40. Recommendations for the safe handling of parenteral antineoplastic drugs.
Washington, DC: Division of Safety: National Institutes of Health; 1983. US Dept
of Health and Human Services, Public Health Service publication NIH 83-2621. 41.
AMA Council on Scientific Affairs. Guidelines for handling parenteral
antineoplastics. JAMA. 1985;253:1590-1591.
42. National Study Commission on Cytotoxic Exposure. Recommendations for
Handling Cytotoxic Agents. 1987. Available from Louis P. Jeffrey, Chairman,
National Study Commission on Cytotoxic Exposure. Massachusetts College of
Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA, 02115.
43. Clinical Oncological Society of Australia. Guidelines and recommendations
for safe handling of antineoplastic agents. Med J Australia. 1983;1:426-428.
44. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a
report from the Mount Sinai Medical Center. CA-A Cancer J for Clin. 1983;33:258-
263.
45. American Society of Hospital Pharmacists. ASHP technical assistance bulletin
on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47:1033-1049.
46. Yodaiken RE, Bennett D. OSHA work-practice guidelines for personnel dealing
with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm. 1986;43:1193-1204.
************************************************************************