Chlorambucil (Monograph)

Brand name: Leukeran
Drug class: Antineoplastic Agents
- Alkylating Agents
VA class: AN100
CAS number: 305-03-3

Medically reviewed by Drugs.com on Jun 21, 2023. Written by ASHP.

Introduction

Antineoplastic agent; nitrogen mustard derivative; alkylating agent.¹⁰⁷

Uses for Chlorambucil

Chronic Lymphocytic Leukemia (CLL)

Treatment of choice (with or without corticosteroids) for adult CLL.^{106 108}

Hodgkin’s Disease

Treatment of adult Hodgkin’s disease;¹⁰⁷ combination regimen that does not include chlorambucil currently is preferred.¹⁰⁶

Non-Hodgkin’s Lymphoma

Treatment (with or without corticosteroids) of indolent, noncontiguous stage II–IV adult non-Hodgkin’s lymphomas (e.g., follicular lymphoma).^b

Not curative; rate of relapse is constant over time, even in complete responders.^b

Optimal treatment as yet unknown; defer treatment in asymptomatic patient and monitor carefully.^b

Waldenström’s Macroglobulinemia

Drug of choice (with or without prednisone) for Waldenström’s macroglobulinemia^{† [off-label]}.^{a b d}

Minimal-change Nephrotic Syndrome

Has been used for the treatment of childhood minimal-change nephrotic syndrome^{† [off-label]}.^a

Second-line agent; use only in those with severe, corticosteroid-dependent or frequently relapsing disease who are intolerant of corticosteroid therapy or whose disease is corticosteroid resistant.^a

Some clinicians prefer cyclophosphamide to chlorambucil.^a

Chlorambucil Dosage and Administration

General

• Optimize results and minimize adverse effects by basing dose on clinical and hematologic response, patient tolerance, and other chemotherapy or irradiation being used.¹⁰⁷

• Consult specialized references for procedures for proper handling and disposal of antineoplastic drugs.¹⁰⁷

Administration

Oral Administration

Administer continuously (as single daily doses) or intermittently (daily for 7 or 10 days every 6 weeks or as biweekly or once-monthly pulse doses).^{107 a d}

May administer high doses in intermittent regimens at bedtime with antiemetics to minimize adverse GI effects.^a

Dosage

Pediatric Patients

Minimal-change Nephrotic Syndrome† [off-label]

Oral

Usual dosage: 0.1–0.2 mg/kg once daily with varying dosages of prednisone for 8–12 weeks; additional course of therapy may be necessary.^a

Adults

Reduce initial dosage if administered within 4 weeks after full course of radiation therapy or myelosuppressive drugs or if pretreatment leukocyte or platelet counts are depressed from bone marrow disease.^{107 a}

CLL

Oral

Continuous regimen: 0.1–0.2 mg/kg (4–10 mg daily for average patient) given as a single daily dose; usually requires only 0.1 mg/kg daily.¹⁰⁷

Biweekly (once every 2 weeks) regimen: initially, 0.4 mg/kg; increase doses by 0.1 mg/kg every 2 weeks until a response and/or myelosuppression occurs.^a Adjust subsequent dosages to produce mild myelosuppression.^a

Once-monthly regimen: initially, 0.4 mg/kg; increase doses by 0.2 mg/kg every 4 weeks until a response and/or myelosuppression occurs.^a Adjust subsequent dosages to produce mild myelosuppression.^a

Therapy usually continued for 3–12 months regardless of regimen and schedule used.^a Generally discontinued after 1 year and restarted when the disease relapses (in patients who achieved a complete remission) or continued as needed (in those who achieved only a partial response).^a

Hodgkin’s Disease

Oral

Usual dosage: 0.1–0.2 mg/kg given as a single daily dose for 3–6 weeks; usually requires 0.2 mg/kg daily.¹⁰⁷

Non-Hodgkin’s Lymphoma

Oral

Usual dosage: 0.1–0.2 mg/kg given as a single daily dose for 3–6 weeks; usually requires only 0.1 mg/kg daily.¹⁰⁷

Waldenström’s Macroglobulinemia† [off-label]

Oral

Continuous therapy: 0.1 mg/kg daily.^d

Intermittent therapy: 0.3 mg/kg daily for 7 days every 6 weeks.^d

Combination therapy: chlorambucil (8 mg/m² daily) and prednisone (40 mg/m² daily) for 10 days every 6 weeks.^{a d}

Therapy usually continued for at least several months regardless of regimen used; optimal duration unknown.^d

Prescribing Limits

Pediatric Patients

Minimal-change Nephrotic Syndrome† [off-label]

Oral

Maximum total dosage during a single course of therapy: 8.2–14 mg/kg.^a

Adults

Oral

Daily dose should not exceed 0.1 mg/kg (about 6 mg for average patient) in the presence of lymphocytic infiltration of the bone marrow or hypoplastic bone marrow.¹⁰⁷

Cautions for Chlorambucil

Contraindications

• Known hypersensitivity to chlorambucil or any ingredient in the formulation.¹⁰⁷

• Disease resistant to prior chlorambucil therapy.¹⁰⁷

Warnings/Precautions

Warnings

Carcinogenicity

Possible leukemia or secondary malignancies; assess risk/benefits of therapy.¹⁰⁷

Not recommended by manufacturer for the treatment of nonmalignant diseases.¹⁰⁷

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm (e.g., unilateral renal agenesis); avoid pregnancy during therapy.¹⁰⁷ If used during pregnancy or if patient becomes pregnant, apprise of potential fetal hazard.¹⁰⁷

Fertility

High incidence of sterility (generally irreversible^d ) in prepubertal and pubertal males; potential for prolonged or permanent azoospermia in adult males.¹⁰⁷

Amenorrhea reported in females.¹⁰⁷

Sensitivity Reactions

Possible angioedema, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and urticaria.¹⁰⁷

Potential for cross-sensitivity (rash) between chlorambucil and other alkylating agents.^a

Discontinue promptly if skin reaction develops.¹⁰⁷

General Precautions

Hematologic Effects

Slowly progressive lymphopenia is common; return to normal lymphocyte counts generally occurs rapidly after completion of therapy.¹⁰⁷

Possible dose-dependent, reversible neutropenia after third week of continuous therapy and continuing for up to 10 days after last dose.¹⁰⁷

Risk of irreversible bone marrow damage increases rapidly with total dose ≥6.5 mg/kg in 1 course of continuous dosing regimen.^{107 a}

Adverse hematologic effects may be less severe with intermittent dosing than with continuous dosing.^a

If leukocyte count falls abruptly or leukocyte or platelet counts fall below normal values, decrease chlorambucil dosage; discontinue drug for more severe depression.¹⁰⁷

Seizures

Possible increased risk of seizures in children with nephrotic syndrome and patients receiving high pulse doses of chlorambucil.¹⁰⁷

Use with caution in patients with a history of seizures or head trauma or those receiving other potentially epileptogenic drugs.¹⁰⁷

Prior Irradiation or Myelosuppressive Therapy

Possible additive myelosuppressive effects; do not administer at full dosages within 4 weeks after a full course of radiation therapy or myelosuppressive drugs.¹⁰⁷

Adequate Patient Evaluation and Monitoring

Monitor hematologic status carefully.¹⁰⁷

Perform weekly CBC; do not allow >2 weeks to elapse between clinical/hematologic evaluations.¹⁰⁷ During first 3–6 weeks of continuous therapy, obtain WBC count 3 or 4 days after each weekly CBC.¹⁰⁷

Immunization

Avoid administration of live vaccines to immunocompromised patients.¹⁰⁷

Specific Populations

Pregnancy

Category D.¹⁰⁷ (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Not known whether chlorambucil is distributed into milk; discontinue nursing or the drug.¹⁰⁷

Pediatric Use

Safety and efficacy not established in pediatric patients;¹⁰⁷ however, has been used when benefits thought to outweigh risks.^a

Possible increased risk of seizures in children with nephrotic syndrome; use with caution in those with a history of seizure disorder or head trauma or receiving concomitant therapy with drugs that lower seizure threshold.¹⁰⁷

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults;¹⁰⁷ titrate dosage carefully, due to greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.¹⁰⁷

Common Adverse Effects

Bone marrow suppression.¹⁰⁷

Chlorambucil Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed from GI tract.¹⁰⁷

Distribution

Extent

Not fully characterized.¹⁰⁷

Apparently crosses the placenta.¹⁰⁷ Not known whether the drug or its metabolites are distributed into milk.¹⁰⁷

Plasma Protein Binding

Approximately 99% (mainly albumin).¹⁰⁷

Elimination

Metabolism

Rapidly and extensively metabolized in the liver, principally to phenylacetic acid mustard (pharmacologically active).¹⁰⁷ Chlorambucil and phenylacetic acid mustard converted to mono- and dihydroxy derivatives.¹⁰⁷

Elimination Route

Excreted in urine (15–60%) almost completely as metabolites.¹⁰⁷

Half-life

Chlorambucil: 1.3–1.5 hours.¹⁰⁷

Phenylacetic acid mustard: 1.8 hours.¹⁰⁷

Stability

Storage

Oral

Tablets

2–8°C.¹⁰⁷

Actions

• Interferes with DNA replication and transcription of RNA; ultimately results in disruption of nucleic acid function.^a

• Possesses some immunosuppressive activity, principally due to suppression of lymphocytes.^a

• The slowest acting and generally least toxic of the currently available nitrogen mustard derivatives.^a

Advice to Patients

• Risk of hypersensitivity, drug fever, myelosuppression, hepatotoxicity, infertility, seizures, GI toxicity, and secondary malignancies.¹⁰⁷

• Importance of informing clinicians if rash, bleeding, fever, jaundice, persistent cough, seizures, nausea, vomiting, amenorrhea, or unusual lumps or masses occur.¹⁰⁷

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed; necessity for clinicians to advise women to avoid pregnancy.¹⁰⁷

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.¹⁰⁷

• Importance of informing patients of other important precautionary information.¹⁰⁷ (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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