LEUKERAN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for LEUKERAN (LEUKERAN).

How it works

Chlorambucil is a bifunctional alkylating agent that cross-links DNA, primarily at guanine N-7, leading to inhibition of DNA replication and transcription, and subsequent apoptosis of rapidly dividing cells.

What the body does with it

Metabolism	Extensively metabolized in the liver via beta-oxidation to phenylacetic acid mustard, the active metabolite. Also undergoes minor hydrolysis and dechlorination. CYP450 enzymes play a minor role.
Excretion	Primarily hepatic metabolism to phenylacetic acid mustard; renal elimination accounts for approximately 60% of total clearance, with <1% excreted unchanged in urine; biliary/fecal elimination is minimal at <1%.
Half-life	Terminal elimination half-life ranges from 1.5 to 2.5 hours, with the active metabolite phenylacetic acid mustard having a half-life of approximately 1.8 hours. This short half-life necessitates frequent dosing for continuous antitumor effect.
Protein binding	Reversibly bound to albumin and other plasma proteins; reported binding is approximately 90-95%, with the active metabolite slightly less bound at 67-72%.
Volume of Distribution	Apparent volume of distribution is 0.5-0.8 L/kg, indicating distribution into total body water with possible tissue binding; clinically relevant for the drug's prolonged retention in lymphoid tissue.
Bioavailability	Oral bioavailability is approximately 70-100%, with little interindividual variation; completely absorbed from the gastrointestinal tract but undergoes extensive first-pass hepatic metabolism to the active metabolite.
Onset of Action	Oral: Peak plasma concentrations occur 1-2 hours post-dose; clinical effects (e.g., lymphopenia) may be observed within 1-2 weeks of continuous therapy.
Duration of Action	Duration of bone marrow suppression (including lymphopenia) persists for several weeks after drug discontinuation; therapeutic effect on lymphoid malignancies usually requires 3-6 weeks of therapy. Maximal tumor response may take weeks to months.

Classification & Brands

Dosing & administration

Chlorambucil 0.1-0.2 mg/kg orally once daily for 3-6 weeks, or 0.4 mg/kg orally on days 1 and 14 every 28 days for chronic lymphocytic leukemia.

Dosage form	TABLET
Renal impairment	No dose adjustment required for GFR ≥10 mL/min. For GFR <10 mL/min, reduce dose by 50%.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: avoid use.
Pediatric use	0.1-0.2 mg/kg orally once daily for 3-6 weeks; maximum single dose 10 mg.
Geriatric use	Start at lower end of dosing range due to increased risk of myelosuppression; monitor blood counts closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for LEUKERAN (LEUKERAN).

Breastfeeding	Contraindicated during breastfeeding. Chlorambucil is excreted into breast milk; M/P ratio not established. Potential for severe adverse effects in nursing infant including bone marrow suppression and carcinogenesis.
Teratogenic Risk	Pregnancy category D. First trimester: High risk of fetal malformations including skeletal, CNS, and cardiac defects. Second and third trimesters: Risk of intrauterine growth restriction, fetal bone marrow suppression, pancytopenia, and neonatal respiratory distress. Avoid in pregnancy unless no safer alternative.

Warnings & precautions

■ FDA Black Box Warning

None. The FDA does not require a boxed warning for chlorambucil.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to chlorambucil or any component of the formulation","Patients who have demonstrated previous resistance to chlorambucil","Pregnancy (teratogenic effects)"]

Clinical Precautions

Precautions

["Bone marrow suppression (leukopenia, thrombocytopenia, anemia) requiring dose adjustment or discontinuation","Increased risk of secondary malignancies (acute leukemia, myelodysplastic syndrome) with prolonged use","Carcinogenicity in humans","Teratogenicity; avoid use during pregnancy","Seizures (rare) at high doses","Hepatotoxicity","Interstitial pneumonitis (rare)"]

Clinical Tips & Counseling

Drug interactions

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LEUKERAN

Clinical safety rating: caution

Comprehensive clinical and safety monograph for LEUKERAN (LEUKERAN).

How it works

What the body does with it

Metabolism	Extensively metabolized in the liver via beta-oxidation to phenylacetic acid mustard, the active metabolite. Also undergoes minor hydrolysis and dechlorination. CYP450 enzymes play a minor role.
Excretion	Primarily hepatic metabolism to phenylacetic acid mustard; renal elimination accounts for approximately 60% of total clearance, with <1% excreted unchanged in urine; biliary/fecal elimination is minimal at <1%.
Half-life	Terminal elimination half-life ranges from 1.5 to 2.5 hours, with the active metabolite phenylacetic acid mustard having a half-life of approximately 1.8 hours. This short half-life necessitates frequent dosing for continuous antitumor effect.
Protein binding	Reversibly bound to albumin and other plasma proteins; reported binding is approximately 90-95%, with the active metabolite slightly less bound at 67-72%.
Volume of Distribution	Apparent volume of distribution is 0.5-0.8 L/kg, indicating distribution into total body water with possible tissue binding; clinically relevant for the drug's prolonged retention in lymphoid tissue.
Bioavailability	Oral bioavailability is approximately 70-100%, with little interindividual variation; completely absorbed from the gastrointestinal tract but undergoes extensive first-pass hepatic metabolism to the active metabolite.
Onset of Action	Oral: Peak plasma concentrations occur 1-2 hours post-dose; clinical effects (e.g., lymphopenia) may be observed within 1-2 weeks of continuous therapy.
Duration of Action	Duration of bone marrow suppression (including lymphopenia) persists for several weeks after drug discontinuation; therapeutic effect on lymphoid malignancies usually requires 3-6 weeks of therapy. Maximal tumor response may take weeks to months.

Classification & Brands

Dosing & administration

Chlorambucil 0.1-0.2 mg/kg orally once daily for 3-6 weeks, or 0.4 mg/kg orally on days 1 and 14 every 28 days for chronic lymphocytic leukemia.

Dosage form	TABLET
Renal impairment	No dose adjustment required for GFR ≥10 mL/min. For GFR <10 mL/min, reduce dose by 50%.
Liver impairment	Child-Pugh A: no adjustment. Child-Pugh B: reduce dose by 50%. Child-Pugh C: avoid use.
Pediatric use	0.1-0.2 mg/kg orally once daily for 3-6 weeks; maximum single dose 10 mg.
Geriatric use	Start at lower end of dosing range due to increased risk of myelosuppression; monitor blood counts closely.

Use during pregnancy

1st trimester	Consult provider
2nd trimester	Consult provider
3rd trimester	Consult provider

Clinical note

Comprehensive clinical and safety monograph for LEUKERAN (LEUKERAN).

Breastfeeding	Contraindicated during breastfeeding. Chlorambucil is excreted into breast milk; M/P ratio not established. Potential for severe adverse effects in nursing infant including bone marrow suppression and carcinogenesis.
Teratogenic Risk	Pregnancy category D. First trimester: High risk of fetal malformations including skeletal, CNS, and cardiac defects. Second and third trimesters: Risk of intrauterine growth restriction, fetal bone marrow suppression, pancytopenia, and neonatal respiratory distress. Avoid in pregnancy unless no safer alternative.

Warnings & precautions

■ FDA Black Box Warning

None. The FDA does not require a boxed warning for chlorambucil.

Side Effect Profile

Serious Effects

Absolute Contraindications

["Hypersensitivity to chlorambucil or any component of the formulation","Patients who have demonstrated previous resistance to chlorambucil","Pregnancy (teratogenic effects)"]