LEUKERAN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LEUKERAN (LEUKERAN).
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.
| 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. |
| Molecular Weight | 304.22 |
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. |
| 1st trimester | Contraindicated due to risk of teratogenicity and fetal malformations. |
| 2nd trimester | Contraindicated; may cause fetal harm, including growth retardation and bone marrow suppression. |
| 3rd trimester | Contraindicated; use in late pregnancy is associated with neonatal bone marrow suppression and pancytopenia. |
Clinical note
Comprehensive clinical and safety monograph for LEUKERAN (LEUKERAN).
| Placental transfer | Chlorambucil crosses the placenta readily, as evidenced by detection in fetal tissues and cord blood. |
| Breastfeeding | Chlorambucil is excreted into breast milk. Due to potential for serious adverse reactions in nursing infants, including carcinogenesis and myelosuppression, breastfeeding is not recommended during therapy and for at least 2 weeks after the last dose. |
■ FDA Black Box Warning
None. The FDA does not require a boxed warning for chlorambucil.
| Serious Effects |
Hypersensitivity to chlorambucil or any component of the formulationPrior resistance to chlorambucil
| 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) |
| Food/Dietary | No specific food restrictions. Grapefruit and grapefruit juice may theoretically affect metabolism (limited data). Avoid alcohol due to potential hepatotoxicity. |
Loading safety data…
| Lactation Rating |
| L5 |
| 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. |
| Fetal Monitoring | Maternal: Complete blood count (CBC) with differential weekly during therapy, liver and renal function tests monthly. Fetal: Serial ultrasound for growth and anatomy if exposed, fetal echocardiography if first trimester exposure. |
| Fertility Effects | Chlorambucil is gonadotoxic. Male: Oligospermia or azoospermia, potentially irreversible. Female: Ovarian failure, premature menopause, reduced fertility. Risk is dose- and duration-dependent. |
| Clinical Pearls | Leukeran (chlorambucil) is an alkylating agent used primarily in CLL and low-grade NHL. Monitor CBC closely due to myelosuppression; dose reduce for WBC < 4000 or platelets < 100,000. Cumulative dose > 6.5 mg/kg increases risk of secondary leukemia. Avoid live vaccines during treatment. |
| Patient Advice | Take exactly as prescribed, usually once daily with water. · May cause nausea; take with food if upset occurs. · Report signs of infection (fever, sore throat) or unusual bleeding/bruising. · Use effective contraception during treatment and for at least 6 months after. · Avoid live vaccines (e.g., MMR, yellow fever) while on this medication. · Attend all scheduled blood tests to monitor blood counts. |