pharmacopeia
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/api/v1/drug/chlorambucil

Boxed 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).

Mechanism of action

Sourced from openFDA

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.

Indications

Sourced from openFDA
  • 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.ICD-10: C85.90, C95.90

Contraindications

Sourced from openFDA
  • 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.contraindicated

Dosage & administration

Sourced from openFDA

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.

Warnings & precautions

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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.

Adverse reactions

Sourced from openFDA

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).

Use in specific populations

Sourced from openFDA

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.

Pharmacokinetics

Sourced from openFDA
Metabolism
In a study of 12 patients given single oral doses of 0.2 mg/kg of LEUKERAN, the mean dose-adjusted (±SD) plasma chlorambucil C max 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 T max was 0.83 ± 0.53 hours. For the major metabolite, phenylacetic acid mustard (PAAM), the mean dose-adjusted (± SD) plasma C max was 306 ± 73 ng/mL, the AUC was 1204 ± 285 ng.h/mL, mean t½ was 1.8 ± 0.4 hours, and the T max was 1.9 ± 0.7 hours.

Overdosage

Sourced from openFDA

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 LD 50 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.

Approval history

Sourced from openFDA
  • Mar 18, 1957NDANDA010669Waylis Therap

FAERS reports

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Reference statistics only. FAERS reports are voluntarily submitted and are not incidence rates, safety signals, or causal evidence. Counts reflect reporting volume — how often a reaction was reported, not how often it occurs. For decision-grade use, consult openFDA and the FAERS Public Dashboard directly.
3,889 total reports matchedLatest report Share = reports listing the reaction ÷ total matched reports. Rows can sum to >100% because a single report often lists multiple reactions.
  1. 1Neutropenia2747.0%
  2. 2Pneumonia2656.8%
  3. 3Off Label Use2616.7%
  4. 4Pyrexia2376.1%
  5. 5Drug Ineffective1965.0%
  6. 6Thrombocytopenia1914.9%
  7. 7Febrile Neutropenia1624.2%
  8. 8Anaemia1574.0%
  9. 9Disease Progression1544.0%
  10. 10Acute Myeloid Leukaemia1313.4%
  11. 11Dyspnoea1253.2%
  12. 12Infection1233.2%
  13. 13Death1153.0%
  14. 14Progressive Multifocal Leukoencephalopathy1112.9%
  15. 15Nausea1092.8%

Literature

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Recent PubMed references pinned to Chlorambucil as a MeSH major topic. Citations link to pubmed.ncbi.nlm.nih.gov.

Clinical trials

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The 10 most recently updated of 65 ClinicalTrials.gov registrations naming Chlorambucil as an intervention. Registration is not evidence of efficacy or safety — reference crosswalk only.

Frequently asked questions

How does Chlorambucil work?
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.
What is Chlorambucil used for?
According to FDA labeling, Chlorambucil carries indications including: 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.. This is a reference summary of labeled uses, not medical advice or a treatment recommendation.
What class of drug is Chlorambucil?
Chlorambucil is classified as Nitrogen mustard analogues, Alkylating Drug, Alkylating Activity, Decreased DNA Integrity, Decreased DNA Replication.
What are the brand names for Chlorambucil?
Chlorambucil is marketed under brand names including Leukeran.
What are the contraindications for Chlorambucil?
Chlorambucil labeling lists contraindications including: 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.. Always consult the full prescribing information and a clinician.
Note. Data for chlorambucil is illustrative MVP content compiled from public sources. pharmacopeia is for educational and informational use only and is not a substitute for professional medical advice.

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