(klor AM byoo sil)
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Leukeran: 2 mg
Brand Names: U.S.
- Antineoplastic Agent, Alkylating Agent
- Antineoplastic Agent, Alkylating Agent (Nitrogen Mustard)
Alkylating agent; interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA
Rapid and complete (>70%) from GI tract; reduced with food
Vd: ~0.3 L/kg
Hepatic (extensively); primarily to active metabolite, phenylacetic acid mustard
Urine (~20% to 60% within 24 hours, primarily as inactive metabolites, <1% as unchanged drug or phenylacetic acid mustard)
Time to Peak
Within 1 hour; Phenylacetic acid mustard: Within 1.9 ± 0.7 hours
~1.5 hours; Phenylacetic acid mustard: ~1.8 hours
~99%; primarily to albumin
Use: Labeled Indications
Chronic lymphocytic leukemia: Management of chronic lymphocytic leukemia (CLL)
Lymphomas: Management of Hodgkin lymphoma (HL) and non-Hodgkin lymphomas (NHL)
Treatment of nephrotic syndrome (steroid sensitive) in children; treatment of Waldenström's macroglobulinemia
Hypersensitivity to chlorambucil or any component of the formulation; hypersensitivity to other alkylating agents (may have cross-hypersensitivity); prior (demonstrated) resistance to chlorambucil
Canadian labeling: Additional contraindications (not in US labeling): Use within 4 weeks of a full course of radiation or chemotherapy
Note: Reduce initial dose if full-dose radiation or myelotoxic drugs have been administered within the last month. 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): Oral: 0.1 mg/kg/day for 3 to 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)
CLL (off-label dosing): 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 30 mg/m2 day 1 every 2 weeks (in combination with prednisone) (Raphael 1991) or 40 mg/m2 day 1 every 4 weeks until disease progression or complete remission or response plateau for up to a maximum of 12 cycles (Rai 2000)
CLL in previously untreated patients (off-label combinations): Oral:
In combination with obinutuzumab: 0.5 mg/kg on days 1 and 15 every 28 days for 6 cycles (Goede 2014)
In combination with ofatumumab: 10 mg/m2 once daily for 7 days (days 1 to 7) every 28 days for a minimum of 3 cycles and up to 12 cycles or best response (clinical response that did not improve after 3 additional cycles); if necessary, reduce dose to 7.5 mg/m2/day and then to 5 mg/m2/day for hematologic toxicity (Hillmen 2015)
Hodgkin lymphoma: Oral: 0.2 mg/kg/day for 3 to 6 weeks
Non-Hodgkin lymphomas (NHL): Oral: 0.1 mg/kg/day for 3 to 6 weeks
Waldenström macroglobulinemia (off-label use): Oral: 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)
Refer to adult dosing. Begin at the lower end of dosing range(s)
Nephrotic syndrome, steroid sensitive (off-label use): Oral: 0.2 mg/kg once daily for ~8 weeks (Hodson 2010)
Dosing: Renal Impairment
There are no dosage adjustments provided in the 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 adjustments have been recommended: Adults:
CrCl >50 mL/minute: No adjustment necessary.
CrCl 10 to 50 mL/minute: Administer 75% of dose.
CrCl <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: Hepatic Impairment
Chlorambucil undergoes extensive hepatic metabolism. Although dosage reduction should be considered in patients with hepatic impairment, there are no dosage adjustments provided in the manufacturer's labeling (data is insufficient).
Dosing: Adjustment for Toxicity
Skin reactions: Discontinue treatment
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.
ASCO Guidelines for appropriate chemotherapy dosing in obese adults with cancer: Utilize patient’s actual body weight (full weight) for calculation of body surface area- or weight-based dosing, particularly when the intent of therapy is curative; manage regimen-related toxicities in the same manner as for nonobese patients; if a dose reduction is utilized due to toxicity, consider resumption of full weight-based dosing with subsequent cycles, especially if cause of toxicity (eg, hepatic or renal impairment) is resolved (Griggs, 2012). Note: The manufacturer recommends the maximum dose should not exceed 0.1 mg/kg/day if maintenance therapy is required and with bone marrow infiltration.
A 2 mg/mL oral suspension may be prepared 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):616-618.6846371Nahata MC, Pai VB, and Hipple TF. Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.
Oral: May be administered as a single daily dose.
Store in refrigerator at 2°C to 8°C (36°F to 46°F).
BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification
Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). 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. Consider therapy modification
Lenograstim: Antineoplastic Agents may diminish the therapeutic effect of Lenograstim. Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination
Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification
Palifermin: May enhance the adverse/toxic effect of Antineoplastic Agents. Specifically, the duration and severity of oral mucositis may be increased. Management: Do not administer palifermin within 24 hours before, during infusion of, or within 24 hours after administration of myelotoxic chemotherapy. Consider therapy modification
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination
Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy
Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). 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. Avoid combination
Frequency not defined.
Central nervous system: Drug fever, peripheral neuropathy
Dermatologic: Allergic skin reaction, skin rash, urticaria
Endocrine & metabolic: Amenorrhea
Gastrointestinal: Diarrhea (infrequent), nausea (infrequent), oral mucosa ulcer (infrequent), vomiting (infrequent)
Genitourinary: Azoospermia, cystitis (sterile), infertility
Hematologic & oncologic: Anemia, bone marrow depression, bone marrow failure (irreversible), leukemia (secondary), leukopenia, lymphocytopenia, malignant neoplasm (secondary), neutropenia (onset: 3 weeks; recovery: 10 days after last dose), pancytopenia, thrombocytopenia
Hepatic: Hepatotoxicity, jaundice
Hypersensitivity: Angioedema, hypersensitivity reaction
Respiratory: Interstitial pneumonitis, pulmonary fibrosis
1% (Limited to important or life-threatening): Agitation, ataxia, confusion, erythema multiforme, flaccid paresis, seizure (focal/generalized), hallucination, muscle twitching, myoclonus, SIADH (syndrome of inappropriate antidiuretic hormone secretion), Stevens-Johnson syndrome, toxic epidermal necrolysis, tremor
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, toxic epidermal necrolysis) have been reported; discontinue promptly if skin reaction occurs.
• Hepatic impairment: Chlorambucil is primarily metabolized in the liver. Dosage reductions should be considered in patients with hepatic impairment.
Concurrent drug therapy issues:
• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Vaccines: Avoid administration of live vaccines to immunocompromised patients.
Liver function tests, CBC with differential (weekly, with WBC monitored twice weekly during the first 3 to 6 weeks of treatment)
Pregnancy Risk Factor
Animal reproduction 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.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience mouth sores, lack of appetite, or diarrhea. Have patient report immediately to prescriber signs of infection, signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), burning or numbness feeling, change in balance, hallucinations, seizures, shortness of breath, confusion, tremors, twitching, severe loss of strength and energy, agitation, amenorrhea, nausea, vomiting, skin growths, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
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- Drug class: alkylating agents
Other brands: Leukeran