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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(klor AM byoo sil)
Generic Available (U.S.)
No
Index Terms
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, non-Hodgkin's lymphomas (NHL)
Use: Unlabeled
Treatment of nephrotic syndrome (steroid sensitive) in children, treatment of Waldenström's macroglobulinemia
Pregnancy Risk Factor
D
Pregnancy Considerations
Animal studies have demonstrated teratogenicity. Chlorambucil crosses the human placenta. Following exposure during the first trimester, case reports have noted adverse renal effects (unilateral agenesis). Women of childbearing potential should avoid becoming pregnant while receiving treatment. [U.S. Boxed Warning]: Affects human fertility; probably mutagenic and teratogenic as well; chromosomal damage has been documented. Reversible and irreversible sterility (when administered to prepubertal and pubertal males), azoospermia (in adult males) and amenorrhea (in females) have been observed. Fibrosis, vasculitis and depletion of primordial follicles have been noted on autopsy of the ovaries.
Lactation
Excretion in breast milk unknown/not recommended
Breast-Feeding Considerations
According to the manufacturer, the decision to continue or discontinue breast-feeding during therapy should take into account the risk of exposure to the infant and the benefits of treatment to the mother.
Contraindications
Hypersensitivity to chlorambucil or any component of the formulation; hypersensitivity to other alkylating agents (may have cross-hypersensitivity); prior (demonstrated) resistance to chlorambucil
Warnings/Precautions
Boxed warnings:
• Bone marrow suppression: See “Concerns related to adverse effects” below.
• Fertility effects: See “Concerns related to adverse effects” below.
• Secondary malignancy: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
Concerns related to adverse effects:
• Bone marrow suppression: [U.S. Boxed Warning]: May cause severe bone marrow suppression; neutropenia may be severe. Reduce initial dosage if patient has received myelosuppressive or radiation therapy within the previous 4 weeks, or has a depressed baseline leukocyte or platelet count. Irreversible bone marrow damage may occur with total doses approaching 6.5 mg/kg. Progressive lymphopenia may develop (recovery is generally rapid after discontinuation).
• Fertility effects: [U.S. Boxed Warning]: Affects human fertility; probably mutagenic and teratogenic as well; chromosomal damage has been documented. Reversible and irreversible sterility (when administered to prepubertal and pubertal males), azoospermia (in adult males) and amenorrhea (in females) have been observed.
• Secondary malignancy: [U.S. Boxed Warning]: Carcinogenic; acute myelocytic leukemia and secondary malignancies may be associated with chronic therapy. Duration of treatment and higher cumulative doses are associated with a higher risk for development of leukemia.
• Seizures: Have been observed with use; patients with a history of nephrotic syndrome and high pulse doses are at higher risk of seizures. Use with caution in patients with a history of seizure disorder or head trauma.
• Skin reactions: Rare instances of severe skin reactions (eg, erythema multiforme, Stevens-Johnson syndrome) have been reported; discontinue promptly if skin reaction occurs.
Disease-related concerns:
• Hepatic impairment: Chlorambucil is primarily metabolized in the liver. Dosage reductions should be considered in patients with hepatic impairment.
Other warnings/precautions:
• Vaccines: Avoid administration of live vaccines to immunocompromised patients.
Adverse Reactions
Frequency not always defined.
Central nervous system: Agitation (rare), ataxia (rare), confusion (rare), drug fever, fever, focal/generalized seizure (rare), hallucinations (rare)
Dermatologic: Angioneurotic edema, erythema multiforme (rare), rash, skin hypersensitivity, Stevens-Johnson syndrome (rare), toxic epidermal necrolysis (rare), urticaria
Endocrine & metabolic: Amenorrhea, infertility, SIADH (rare)
Gastrointestinal: Diarrhea (infrequent), nausea (infrequent), oral ulceration (infrequent), vomiting (infrequent)
Genitourinary: Azoospermia, cystitis (sterile)
Hematologic: Neutropenia (onset: 3 weeks; recovery: 10 days after last dose), bone marrow failure (irreversible), bone marrow suppression, anemia, leukemia (secondary), leukopenia, lymphopenia, pancytopenia, thrombocytopenia
Hepatic: Hepatotoxicity, jaundice
Neuromuscular & skeletal: Flaccid paresis (rare), muscular twitching (rare), myoclonia (rare), peripheral neuropathy, tremor (rare)
Respiratory: Interstitial pneumonia, pulmonary fibrosis
Miscellaneous: Allergic reactions, malignancies (secondary)
Metabolism/Transport Effects
None known.
Drug Interactions
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for agranulocytosis may be increased. Risk X: Avoid combination
Coccidioidin Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioidin Skin Test. Risk C: Monitor therapy
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk D: Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinial infections may develop. Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Food: Absorption is decreased when administered with food.
Storage
Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light.
Mechanism of Action
Alkylating agent; interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA
Pharmacodynamics/Kinetics
Absorption: Rapid and complete (>70%); reduced with food
Distribution: Vd: ~0.3 L/kg
Protein binding: ~99%; primarily to albumin
Metabolism: Hepatic (extensively); primarily to active metabolite, phenylacetic acid mustard
Half-life elimination: ~1.5 hours; Phenylacetic acid mustard: ~1.8 hours
Time to peak, plasma: Within 1 hour; Phenylacetic acid mustard: 1.2-2.6 hours
Excretion: Urine (~20% to 60%, primarily as inactive metabolites, <1% as unchanged drug or phenylacetic acid mustard)
Dosage
Oral:
Children: Nephrotic syndrome, steroid sensitive (unlabeled use): 0.2 mg/kg once daily for 8 weeks (Hodson, 2010)
Adults: Note: With bone marrow lymphocytic infiltration involvement (in CLL, Hodgkin lymphoma, or NHL), the maximum dose is 0.1 mg/kg/day. While short treatment courses are preferred, if maintenance therapy is required, the maximum dose is 0.1 mg/kg/day.
Chronic lymphocytic leukemia (CLL):
Labeled dosing: 0.1 mg/kg/day for 3-6 weeks or 0.4 mg/kg pulsed doses administered intermittently, biweekly, or monthly (increased by 0.1 mg/kg/dose until response/toxicity observed)
Unlabeled dosing: 30 mg/m2 day 1 every 2 weeks (in combination with prednisone) (Raphael, 1991) or 0.4 mg/kg day 1 every 2 weeks; if tolerated may increase by 0.1 mg/kg with each treatment course to a maximum dose of 0.8 mg/kg and maximum of 24 cycles (Eichhorst, 2009) or 40 mg/m2 day 1 every 4 weeks for up to 12 cycles or until disease progression or complete remission or response plateau (Rai, 2000)
Hodgkin lymphoma: 0.2 mg/kg/day for 3-6 weeks
Non-Hodgkin's lymphomas (NHL): 0.1 mg/kg/day for 3-6 weeks
Waldenström's macroglobulinemia (unlabeled use): 0.1 mg/kg/day (continuously) for at least 6 months or 0.3 mg/kg/day for 7 days every 6 weeks for at least 6 months (Kyle, 2000)
Elderly: Refer to adult dosing; begin at the lower end of dosing range(s)
Dosage adjustment for toxicity:
Skin reactions: Discontinue treatment
Hematologic:
WBC or platelets below normal: Reduce dose
Severely depressed WBC or platelet counts: Discontinue
Persistently low neutrophil or platelet counts or peripheral lymphocytosis: May be suggestive of bone marrow infiltration; if infiltration confirmed, do not exceed 0.1 mg/kg/day.
Concurrent or within 4 weeks (before or after) of chemotherapy/radiotherapy: Initiate treatment cautiously; reduce dose; monitor closely.
Dosing adjustment in renal impairment: No dosage adjustment provided in manufacturer's labeling; however, renal elimination of unchanged chlorambucil and active metabolite (phenylacetic acid mustard) is minimal and renal impairment is not likely to affect elimination. The following recommendations have been used by some clinicians: Adults:
Aronoff, 2007:
Clcr >50 mL/minute: No adjustment necessary
Clcr 10-50 mL/minute: Administer 75% of dose
Clcr <10 mL/minute: Administer 50% of dose
Peritoneal dialysis (PD): Administer 50% of dose
Kintzel, 1995: Based on the pharmacokinetics, dosage adjustment is not indicated
Dosing adjustment in hepatic impairment: Chlorambucil undergoes extensive hepatic metabolism. Although dosage reduction should be considered in patients with hepatic impairment, no dosage adjustment is provided in the manufacturer's labeling (data is insufficient).
Dosage: Combination Regimens
Leukemia, chronic lymphocytic:
CHL + PRED
CP (Leukemia)
Lymphoma, Hodgkin: ChIVPP (Hodgkin)
Administration: Oral
Usually administered as a single dose; preferably on an empty stomach.
Monitoring Parameters
Liver function tests, CBC with differential (weekly, with WBC monitored twice weekly during the first 3-6 weeks of treatment), serum uric acid
Patient Education
Maintain adequate hydration, unless instructed to restrict fluid intake. Avoid alcohol and acidic, spicy, or hot foods. May cause menstrual irregularities and/or sterility. You will be more susceptible to infection. May cause nausea, vomiting, or mouth sores. Report CNS changes (agitation, confusion, hallucinations, seizures); easy bruising or bleeding; unusual rash; persistent nausea, vomiting, or mouth sores; yellowing of skin or dark urine; or respiratory difficulty.
Geriatric Considerations
Toxicity to immunosuppressives is increased in the elderly. Start with lowest recommended adult doses. Signs of infection, such as fever and rise in WBCs, may not occur. Lethargy and confusion may be more prominent signs of infection.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Stomatitis.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May rarely produce agitation, confusion, and hallucinations
Mental Health: Effects on Psychiatric Treatment
Myelosuppression is common; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Use caution in presence of seizure disorder or bone marrow suppression. Monitor for hematologic myelosuppression, hypersensitivity rash, drug fever, seizures, gastrointestinal upset, and hepatotoxicity. Teach sexually-active female patients necessity for contraception.
Oncology: Emetic Potential
Very low (<10%)
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral:
Leukeran®: 2 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Leukeran)
2 mg (30): $134.99
Extemporaneously Prepared
Hazardous agent: Use appropriate precautions for handling and disposal.
A 2 mg/mL oral suspension may be made with tablets. Crush sixty 2 mg tablets in a mortar and reduce to a fine powder. Add small portions of methylcellulose 1% and mix to a uniform paste (total methylcellulose: 30 mL); mix while adding simple syrup in incremental proportions to almost 60 mL; transfer to a graduated cylinder, rinse mortar and pestle with simple syrup, and add quantity of vehicle sufficient to make 60 mL. Transfer contents of graduated cylinder to an amber prescription bottle. Label “shake well”, “refrigerate”, and “protect from light”. Stable for 7 days refrigerated.
Dressman JB and Poust RI, “Stability of Allopurinol and of Five Antineoplastics in Suspension,” Am J Hosp Pharm, 1983, 40(4):616-8.
Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
References
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 98.
Eichhorst BF, Busch R, Stilgenbauer S, et al, “First-Line Therapy With Fludarabine Compared With Chlorambucil Does Not Result in a Major Benefit for Elderly Patients With Advanced Chronic Lymphocytic Leukemia,” Blood, 2009, 114(16):3382-91.
Hodson EM, Willis NS, and Craig JC, “Non-Corticosteroid Treatment for Nephrotic Syndrome in Children (Review),” Cochrane Database Syst Rev, 2010, (4):CD002290.
Kyle RA, Greipp PR, Gertz MA, et al, “Waldenström's Macroglobulinemia: A Prospective Study Comparing Daily With Intermittent Oral Chlorambucil,” Br J Haematol, 2000, 108(4):737-42.
Rai KR, Peterson BL, Appelbaum FR, et al, “Fludarabine Compared With Chlorambucil as Primary Therapy for Chronic Lymphocytic Leukemia,” N Engl J Med, 2000, 343(24):1750-7.
Raphael B, Andersen JW, Silber R, et al, “Comparison of Chlorambucil and Prednisone Versus Cyclophosphamide, Vincristine, and Prednisone as Initial Treatment for Chronic Lymphocytic Leukemia: Long-Term Follow-Up of an Eastern Cooperative Oncology Group Randomized Clinical Trial,” J Clin Oncol, 1991, 9(5):770-6.
Robinson RF, Nahata MC, Mahan JD, “Management of Nephrotic Syndrome in Children,” Pharmacotherapy, 2003, 23(8):1021-36.
Wagner AM, Brunet S, Puig J, et al, “ Chlorambucil-Induced Inappropriate Antidiuresis in Man With Chronic Lymphocytic Leukemia,” Ann Hemat, 1999, 78(1):37-8.
International Brand Names
Lexi-Comp.com
Last full review/revision January 2012
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