Bone marrow suppression:
Chlorambucil can severely suppress bone marrow function.
Chlorambucil is a carcinogen in humans. Chlorambucil is probably mutagenic and teratogenic in humans. Chlorambucil produces human infertility.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Leukeran: 2 mg
Mechanism of Action
Chlorambucil is an alkylating agent that interferes with DNA replication and RNA transcription by alkylation and cross-linking the strands of DNA, inducing cellular apoptosis.
Rapid and complete (>70%) from GI tract; reduced with food
Vd: ~0.31 L/kg
Hepatic (extensively); primarily to active metabolite, phenylacetic acid mustard; chlorambucil and phenylacetic acid mustard undergo oxidative degradation
Urine (~20% to 60% within 24 hours, primarily as inactive metabolites, <1% as unchanged drug or phenylacetic acid mustard)
Time to Peak
Chlorambucil: Within 1 hour; Phenylacetic acid mustard: 1.9 ± 0.7 hours
Chlorambucil: ~1.5 hours; Phenylacetic acid mustard: 1.8 ± 0.4 hours
~99%; primarily to albumin
Use: Labeled Indications
Chronic lymphocytic leukemia: Management of chronic lymphocytic leukemia
Hodgkin lymphoma: Management of Hodgkin lymphoma
Non-Hodgkin lymphoma: Management of non-Hodgkin lymphomas
Use: Off Label
Idiopathic membranous nephropathybyes
Data from a multicenter, randomized, controlled study support the use of chlorambucil (alternating with prednisolone) for the treatment of progressive idiopathic membranous nephropathy in patients with a decline in renal function Howman 2013.
Based on the Kidney Disease: Improving Global Outcomes clinical practice guideline for glomerulonephritis, chlorambucil may be used in the treatment of idiopathic membranous nephropathy (in combination with corticosteroids), although cyclophosphamide may be preferred.
Data from case reports, retrospective reviews, and clinical experience support the use of chlorambucil (as monotherapy or in combination with corticosteroids) in the treatment of necrobiotic xanthogranuloma when there is not underlying malignancy Finan 1986, Hilal 2018, Mehregan 1992, Ryan 2012, Szalat 2011, Wells 2004, Wood 2009. A systematic review summarizing reported literature of chlorambucil in the treatment of necrobiotic xanthogranuloma further supports the use of chlorambucil as a single agent following surgery when there is not underlying malignancy, and with or without prednisone in patients with underlying malignancy Miguel 2017.
Waldenström macroglobulinemia, alternative agentc
Data from a dose-comparison study suggests that chlorambucil may be of benefit in the treatment of Waldenström macroglobulinemia Kyle 2000. A study comparing chlorambucil to fludarabine demonstrated that fludarabine is more effective in the treatment of Waldenström macroglobulinemia, although toxicities were higher with fludarabine Leblond 2013. A systematic review and clinical experience suggest that chlorambucil may be an option for patients unable to tolerate more aggressive therapies Gertz 2019, Lepretre 2016.
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 the US labeling): Use within 4 weeks of a full course of radiation or chemotherapy
Dosage and Administration
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 chronic lymphocytic leukemia [CLL], Hodgkin lymphoma, or non-Hodgkin lymphoma [NHL]), the manufacturer recommends a maximum dose of 0.1 mg/kg/day; while short treatment courses are preferred, if maintenance therapy is required, the manufacturer recommends a maximum dose of 0.1 mg/kg/day.
Chronic lymphocytic leukemia: Oral:
Chronic lymphocytic leukemia in previously untreated patients (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 0.5 mg/kg on days 1 and 15 every 28 days for 6 cycles (Goede 2014) 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).
Chronic lymphocytic leukemia in previously untreated patients (off-label combinations):
Chlorambucil-obinutuzumab: 0.5 mg/kg on days 1 and 15 every 28 days for 6 cycles (Goede 2014).
Chlorambucil-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).
Chlorambucil-rituximab: 10 mg/m2 once daily for 7 days (days 1 to 7) every 28 days for 6 to 12 cycles (Hillmen 2014).
Manufacturer’s labeling: 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).
Hodgkin lymphoma: Oral: ChlVPP regimen: 6 mg/m2 once daily (maximum 10 mg/day) on days 1 to 14 every 28 days (in combination with vinblastine, procarbazine, and prednisolone) until complete remission plus 2 cycles (Selby 1990) or 6 mg/m2 once daily on days 1 to 14 every 28 days (in combination with vinblastine, procarbazine, and prednisone) for 6 cycles (Vose 1991).
Idiopathic membranous nephropathy (alternative agent) (off-label use): Oral: 0.15 to 0.2 mg/kg/day during months 2, 4, and 6 (alternating with prednisolone/methylprednisolone during months 1, 3, and 5) (Howman 2013; KDIGO 2012). Note: Due to potential adverse events, other agents may be preferred over chlorambucil.
Necrobiotic xanthogranuloma (off-label use; based on limited data): Oral: 2 to 4 mg once daily either with or without systemic corticosteroids (Finan 1986; Hilal 2018; Mehregan 1992; Miguel 2017) or 10 mg once daily for 14 days of a 28-day treatment cycle for 8 cycles (Ryan 2012) or 10 mg once daily, reduced to 2 mg once daily (in combination with prednisone) (Wells 2004).
Non-Hodgkin lymphomas: Oral:
Follicular lymphoma (off-label dosing): 6 mg/m2 once daily during weeks 1 to 6, followed 8 weeks later (if response occurred) by 6 mg/m2 once daily for 2 weeks of a 4-week cycle for 4 cycles (in combination with rituximab) (Martinelli 2003; Martinelli 2015).
Mucosa-associated lymphoid tissue lymphoma (off-label dosing): 6 mg/m2 once daily during weeks 1 to 6, followed by 6 mg/m2 once daily for 2 weeks of a 4-week cycle for up to 4 cycles (in combination with rituximab) (Zucca 2017).
Manufacturer’s labeling: 0.1 mg/kg/day for 3 to 6 weeks.
Waldenström macroglobulinemia, alternative agent (off-label use): Oral: 8 mg/m2 (6 mg/m2 in patients >75 years of age) once daily for 10 days every 28 days for up to 12 cycles (Leblond 2013) or 0.1 mg/kg/day (continuously) for at least 6 months (Kyle 2000) 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)
Note: For oncologic uses, dosing and frequency may vary by protocol and/or treatment phase; refer to specific protocol.
Hodgkin lymphoma: Limited data available: Infants ≥7 months, Children, and Adolescents: ChlVPP regimen: Oral: 6 mg/m2/day on days 1 to 14 of a 28-day cycle for 6 to 10 cycles in combination with vinblastine, procarbazine, and prednisolone (Atra 2002; Capra 2007; Hall 2007; Stoneham 2007)
Nephrotic syndrome; frequently relapsing steroid-sensitive: Limited data available: Children and Adolescents: Oral: 0.1 to 0.2 mg/kg/day once daily for 8 weeks (maximum cumulative dose: 11.2 mg/kg) (Baluarte 1978; Hodson 2010; KDIGO 2012); Note: Chlorambucil is not a preferred agent due to a higher incidence of adverse effects with no greater efficacy (Gipson 2009).
Dosing adjustment for toxicity: The presented dosing adjustments are based on experience in adult patients; specific recommendations for pediatric patients are limited. Refer to specific protocol for management.
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 in adults
Concurrent or within 4 weeks (before or after) of chemotherapy/radiotherapy: Initiate treatment cautiously; reduce dose; monitor closely.
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 (excludes leukemias): 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).
Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification
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
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. 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. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
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. Management: Avoid the use of lenograstim 24 hours before until 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification
Lipegfilgrastim: Antineoplastic Agents may diminish the therapeutic effect of Lipegfilgrastim. Management: Avoid concomitant use of lipegfilgrastim and myelosuppressive cytotoxic chemotherapy. Lipegfilgrastim should be administered at least 24 hours after the completion of myelosuppressive cytotoxic chemotherapy. Consider therapy modification
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
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
Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy
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
Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy
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
Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification
Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). 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. Consider therapy modification
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy
Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Avoid combination
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. Exceptions: Smallpox and Monkeypox Vaccine (Live). 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%, postmarketing, and/or case reports: Agitation, ataxia, confusion, erythema multiforme, flaccid paralysis, 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: [US Boxed Warning]: Chlorambucil 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: [US Boxed Warning]: Chlorambucil causes human infertility; is probably mutagenic and teratogenic in humans 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: [US Boxed Warning]: Chlorambucil is a human carcinogen; 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.
Monitor LFTs, CBC with differential (weekly, with WBC monitored twice weekly during the first 3 to 6 weeks of treatment). Monitor adherence.
Pregnancy Risk Factor
Following exposure during the first trimester, case reports have noted adverse renal effects (unilateral agenesis) in the newborn.
[US Boxed Warning]: Chlorambucil is probably mutagenic and teratogenic in humans. Chlorambucil produces human infertility. 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. Women of childbearing potential should avoid becoming pregnant while receiving treatment.
What is this drug used for?
- It is used to treat leukemia.
- It is used to treat lymphoma.
- It may be given to you for other reasons. Talk with the doctor.
Frequently reported side effects of this drug
- Mouth sores
- Lack of appetite
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
- Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; 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
- Sensing things that seem real but are not
- Shortness of breath
- Severe loss of strength and energy
- No menstrual periods
- Skin growths
- Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
- Signs of a significant reaction like 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. Talk to your doctor if you have questions.
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