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  • CLASSES

    Nitrogen Mustard Analogs

    BOXED WARNING

    New primary malignancy

    Chlorambucil may be mutagenic in humans. New primary malignancy (e.g., leukemia) has been reported in patients who received chlorambucil for malignant and nonmalignant diseases; in many cases, patients also received chemotherapy or radiation.Due to its carcinogenic effects chlorambucil should not be administered to patients with a neoplastic disease other than chronic lymphocytic leukemia or lymphoma. Although the exact risk cannot be quantified, chlorambucil therapy has been associated with secondary leukemia. The risk of secondary malignancy due to alkylating agents such as chlorambucil is associated with the length of therapy (chronicity) and large cumulative doses. The potential benefits of chlorambucil therapy must be considered on an individual basis against the risk of secondary leukemia.

    Anemia, bone marrow suppression, leukopenia, neutropenia, radiation therapy, thrombocytopenia

    Bone marrow suppression, anemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia, and pancytopenia have been reported in patients who received chlorambucil. Initiate chlorambucil at a reduced dosage if patients have bone morrow suppression prior to starting therapy. Monitor a complete blood cell (CBC) panel prior to and then weekly during chlorambucil therapy and more frequently during the first 3 to 6 weeks (e.g., white blood cell (WBC) count at 3 or 4 days after each weekly CBC panel). Hematological and clinical examinations should occur at least every 2 weeks. The chlorambucil dosage is adjusted according to patient response and is reduced as soon as there is an abrupt fall in the WBC count. Discontinue therapy if severe leukopenia, neutropenia, or thrombocytopenia occurs. Hematologic toxicity is common, dose limiting, and reversible if chlorambucil is stopped early; however, irreversible bone marrow failure has occurred. Neutropenia typically occurs after the third week of therapy and continues for up to 10 days after the last dose. Severe neutropenia is dose related usually occurring after a total dosage of 6.5 mg/kg or more in one course of therapy with continuous dosing. Use chlorambucil with caution in patients receiving concurrent radiation therapy and/or other cytotoxic drugs, especially within 4 weeks of a full course of radiation therapy or chemotherapy. Do not administer full dosages of chlorambucil during this time period. However, chlorambucil may be given at the usual dosage in patients receiving small doses of focused palliative radiation that is not directed at the bone marrow.

    Pregnancy

    Chlorambucil may cause fetal harm in administered during pregnancy. Females of reproductive potential should be advised to avoid becoming pregnant while receiving chlorambucil treatment. If this drug is used during pregnancy or if the patient becomes pregnant while receiving chlorambucil, the patient should be apprised of the potential risks to the fetus. Animal studies have demonstrated fetal abnormalities (i.e., urogenital malformations in rats); however, there have been no well-controlled trials in pregnant woman. Unilateral renal agenesis has been observed in 2 cases when the mother received chlorambucil during the first trimester.

    Infertility

    Chlorambucil causes chromatid or chromosome damage in humans. Infertility has been reported in patients who received chlorambucil for malignant and nonmalignant diseases; permanent sterility has occurred in both males and females. Prepubertal and pubertal males have an increased risk of becoming sterile following chlorambucil therapy.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral alkylating agent
    Approved for use as palliative treatment of chronic lymphocytic leukemia, Hodgkin lymphoma, and certain non-Hodgkin's lymphomas including lymphosarcoma and giant follicular lymphoma
    Has black box warnings for severe myelosuppression, carcinogenicity, teratogenicity, and infertility

    COMMON BRAND NAMES

    Leukeran

    HOW SUPPLIED

    Leukeran Oral Tab: 2mg

    DOSAGE & INDICATIONS

    For the treatment of chronic lymphocytic leukemia (CLL).
    For the palliative treatment of CLL.
    Oral dosage
    Adults

    0.1 to 0.2 mg/kg orally once daily (average of 4 to 10 mg/day) for 3 to 6 weeks is the usual initial dosage or the dosage for short courses of treatment. Most patients require 0.1 mg/kg daily. Adjust the chlorambucil dosage based on patient response; reduce the dosage when there is an abrupt fall in white blood cell count. The dosage should not exceed 0.1 mg/kg daily (average of about 6 mg/day) in patients with hypoplastic bone marrow or if lymphocytic infiltration of the bone marrow is present. Alternate chlorambucil dosage schedules include intermittent (starting at a single dose of 0.4 mg/kg), biweekly, or once monthly pulse dosing. Doses are usually increased by 0.1 mg/kg until lymphocytosis is controlled or toxicity is observed; subsequent doses are adjusted to result in mild hematologic toxicity. Biweekly or once monthly chlorambucil administration appears to be at least similar in efficacy but with less than or equal hematologic toxicity compared with daily chlorambucil. Maintenance therapy (if needed) should not exceed 0.1 mg/kg daily and may be as low as 0.03 mg/kg daily. Most patients require a dosage of 2 to 4 mg/day or less. Consider discontinuing therapy after maximal control has been achieved; intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.

    For the first-line treatment of CLL, in combination with prednisone†.
    Oral dosage
    Adults

    30 mg/m2 PO on day 1 in combination with prednisone 80 mg PO once daily on days 1 to 5 repeated every 2 weeks for up to 18 months and maximum response was evaluated in a randomized study. Alternatively, chlorambucil 12 mg/m2 PO daily for 7 days plus prednisone 30 mg/m2 PO daily for 7 days repeated every 28 days for up to 6 courses was used in another randomized study.

    For the first-line treatment of CLL, in combination with fludarabine†.
    Oral dosage
    Adults

    Chlorambucil plus fludarabine for the first line treatment of chronic lymphocytic leukemia was associated with significant toxicity in a randomized, 3-arm, phase III study. This study compared single-agent chlorambucil with single-agent fludarabine or fludarabine (20 mg/m2/day IV in days 1 to 5) plus chlorambucil (20 mg/m2 PO on day 1) repeated every 28 days for up to 12 cycles. The combination therapy arm was discontinued because of increased severe and life-threatening adverse effects compared with single-agent fludarabine.

    For the palliative treatment of Hodgkin lymphoma.
    Oral dosage
    Adults

    0.1 to 0.2 mg/kg orally once daily (average of 4 to 10 mg/day) for 3 to 6 weeks is the usual initial dosage or the dosage for short courses of treatment. Most patients require 0.2 mg/kg daily. Adjust the chlorambucil dosage based on patient response; reduce the dosage when there is an abrupt fall in white blood cell count. The dosage should not exceed 0.1 mg/kg daily (average of about 6 mg/day) in patients with hypoplastic bone marrow. Maintenance therapy (if needed) should not exceed 0.1 mg/kg daily and may be as low as 0.03 mg/kg daily. Most patients require a dosage of 2 to 4 mg/day or less. Consider discontinuing therapy after maximal control has been achieved; intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.

    For the palliative treatment of non-Hodgkin's lymphoma (NHL) including lymphosarcoma and giant follicular lymphoma.
    Oral dosage
    Adults

    0.1 to 0.2 mg/kg orally once daily (average of 4 to 10 mg/day) for 3 to 6 weeks is the usual initial dosage or the dosage for short courses of treatment. Most patients require 0.1 mg/kg daily. Adjust the chlorambucil dosage based on patient response; reduce the dosage when there is an abrupt fall in white blood cell count. The dosage should not exceed 0.1 mg/kg daily (average of about 6 mg/day) in patients with hypoplastic bone marrow or if lymphocytic infiltration of the bone marrow is present. Maintenance therapy (if needed) should not exceed 0.1 mg/kg daily and may be as low as 0.03 mg/kg daily. Most patients require a dosage of 2 to 4 mg/day or less. Consider discontinuing therapy after maximal control has been achieved; intermittent therapy reinstituted at time of relapse may be as effective as continuous treatment.

    For the treatment of macroglobulinemia†.
    Oral dosage
    Adults

    Regimens have included chlorambucil 8 mg/m2 PO once daily for 10 days every 6 to 8 weeks.

    For the treatment of nephrotic syndrome†.
    Oral dosage
    Adults, Adolescents, and Children

    0.1 to 0.2 mg/kg PO once daily for 8 to 12 weeks.

    For the treatment of dermatomyositis†, pneumonitis†, lupus nephritis†, or polymyositis† related to systemic lupus erythematosus (SLE)†.
    Oral dosage
    Adults

    Limited data are available describing chlorambucil treatment for systemic lupus, and guidelines for lupus nephritis do not include chlorambucil. The typical dose range is 0.1 to 0.2 mg/kg/day PO with or without concomitant prednisone. Every 2 weeks the dose can be increased by 2 mg/day until clinical response, toxicity, or a total dose of 10 mg/day is reached. Doses of 2 to 12 mg/day PO once daily are usually administered. Other references suggest doses of 4 mg/day PO for 3 months, or, in combination with prednisone, 10 mg/day PO for 2 to 4 weeks then reduced to 2 to 5 mg/day PO.

    For the treatment of rheumatoid arthritis†.
    Oral dosage
    Adults

    Chlorambucil is considered a second line agent in the treatment of rheumatoid arthritis. A dosage of 0.1 to 0.2 mg/kg/day PO has been recommended.

    For the treatment of systemic vasculitis syndromes† including Behcet's syndrome†, Churg-Strauss syndrome†, polyarteritis nodosa†, uveitis†, or granulomatosis with polyangiitis†.
    Oral dosage
    Adults

    0.2 mg/kg PO once daily, then taper over several months to 0.1 mg/kg/day or less.

    For the treatment of immune thrombocytopenic purpura (ITP)†.
    Oral dosage
    Adults

    Chlorambucil has been used in combination with corticosteroids to treat ITP at doses of 0.1 to 0.2 mg/kg/day PO.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    The maximum dosage is dependent on indication, response, and toxicity.

    Geriatric

    The maximum dosage is dependent on indication, response, and toxicity.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Chlorambucil is primarily metabolized in the liver. Consider an initial dose reduction in these patients.

    Renal Impairment

    Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

    ADMINISTRATION

    Hazardous Drugs Classification
    NIOSH 2016 List: Group 1
    NIOSH (Draft) 2020 List: Table 1
    Observe and exercise appropriate precautions for handling, preparation, administration, and disposal of hazardous drugs.
    Use gloves. Cutting, crushing, or otherwise manipulating tablets/capsules will increase exposure.
    Emetic Risk
    Pediatrics: Doses 0.2 mg/kg/day or less: Minimal
    Adults: Minimal/Low
    Administer prn antiemetics as necessary.

    Oral Administration

    To minimize adverse GI effects of single, high chlorambucil doses, administer at bedtime with an antiemetic.

    STORAGE

    Leukeran:
    - Store between 36 to 46 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    New primary malignancy

    Chlorambucil may be mutagenic in humans. New primary malignancy (e.g., leukemia) has been reported in patients who received chlorambucil for malignant and nonmalignant diseases; in many cases, patients also received chemotherapy or radiation.Due to its carcinogenic effects chlorambucil should not be administered to patients with a neoplastic disease other than chronic lymphocytic leukemia or lymphoma. Although the exact risk cannot be quantified, chlorambucil therapy has been associated with secondary leukemia. The risk of secondary malignancy due to alkylating agents such as chlorambucil is associated with the length of therapy (chronicity) and large cumulative doses. The potential benefits of chlorambucil therapy must be considered on an individual basis against the risk of secondary leukemia.

    Hepatic disease

    Use chlorambucil with caution in patients with hepatic disease; it is primarily metabolized in the liver. Monitor patients with hepatic impairment for signs of chlorambucil toxicity. Consider a dose reduction in these patients.

    Anemia, bone marrow suppression, leukopenia, neutropenia, radiation therapy, thrombocytopenia

    Bone marrow suppression, anemia, leukopenia, lymphopenia, neutropenia, thrombocytopenia, and pancytopenia have been reported in patients who received chlorambucil. Initiate chlorambucil at a reduced dosage if patients have bone morrow suppression prior to starting therapy. Monitor a complete blood cell (CBC) panel prior to and then weekly during chlorambucil therapy and more frequently during the first 3 to 6 weeks (e.g., white blood cell (WBC) count at 3 or 4 days after each weekly CBC panel). Hematological and clinical examinations should occur at least every 2 weeks. The chlorambucil dosage is adjusted according to patient response and is reduced as soon as there is an abrupt fall in the WBC count. Discontinue therapy if severe leukopenia, neutropenia, or thrombocytopenia occurs. Hematologic toxicity is common, dose limiting, and reversible if chlorambucil is stopped early; however, irreversible bone marrow failure has occurred. Neutropenia typically occurs after the third week of therapy and continues for up to 10 days after the last dose. Severe neutropenia is dose related usually occurring after a total dosage of 6.5 mg/kg or more in one course of therapy with continuous dosing. Use chlorambucil with caution in patients receiving concurrent radiation therapy and/or other cytotoxic drugs, especially within 4 weeks of a full course of radiation therapy or chemotherapy. Do not administer full dosages of chlorambucil during this time period. However, chlorambucil may be given at the usual dosage in patients receiving small doses of focused palliative radiation that is not directed at the bone marrow.

    Serious rash

    Chlorambucil is contraindicated in patients with a hypersensitivity to it or any component of the product and in patients who have developed resistance to it. A cross-sensitivity can exist between chlorambucil and other alkylating agents, resulting in a hypersensitivity reaction manifested as a serious rash. Additionally, serious rash (i.e., erythema multiforme, toxic epidermal necrolysis) has been reported with chlorambucil therapy; discontinue therapy in patients who develop a serious rash.

    Head trauma, seizure disorder

    Rare, focal and/or generalized seizures have been reported with chlorambucil in children and adults. Seizures have occurred at therapeutic daily doses, with pulse-dosing regimens, and in acute overdose situations. Use chlorambucil with caution in children with nephrotic syndrome (off-label use) and in patients receiving high-dose pulse therapy, receiving concomitant drugs that may also cause seizures, or who have a history of head trauma or seizure disorder.

    Vaccination

    Avoid vaccination with live vaccines during chlorambucil therapy because the antibody response may be suboptimal in immunocompromised patients.

    Pregnancy

    Chlorambucil may cause fetal harm in administered during pregnancy. Females of reproductive potential should be advised to avoid becoming pregnant while receiving chlorambucil treatment. If this drug is used during pregnancy or if the patient becomes pregnant while receiving chlorambucil, the patient should be apprised of the potential risks to the fetus. Animal studies have demonstrated fetal abnormalities (i.e., urogenital malformations in rats); however, there have been no well-controlled trials in pregnant woman. Unilateral renal agenesis has been observed in 2 cases when the mother received chlorambucil during the first trimester.

    Infertility

    Chlorambucil causes chromatid or chromosome damage in humans. Infertility has been reported in patients who received chlorambucil for malignant and nonmalignant diseases; permanent sterility has occurred in both males and females. Prepubertal and pubertal males have an increased risk of becoming sterile following chlorambucil therapy.

    Breast-feeding

    Women should avoid breast-feeding during chlorambucil therapy due to the potential for serious adverse reactions in breastfed infants. It is unknown whether chlorambucil is excreted into breast milk.

    ADVERSE REACTIONS

    Severe

    seizures / Delayed / 0-1.0
    erythema multiforme / Delayed / 0-1.0
    toxic epidermal necrolysis / Delayed / 0-1.0
    Stevens-Johnson syndrome / Delayed / 0-1.0
    pancytopenia / Delayed / Incidence not known
    pulmonary fibrosis / Delayed / Incidence not known
    new primary malignancy / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    teratogenesis / Delayed / Incidence not known

    Moderate

    oral ulceration / Delayed / 1.0-10.0
    myoclonia / Delayed / 0-1.0
    hallucinations / Early / 0-1.0
    ataxia / Delayed / 0-1.0
    confusion / Early / 0-1.0
    paresis / Delayed / 0-1.0
    neutropenia / Delayed / 25.0
    leukopenia / Delayed / Incidence not known
    bone marrow suppression / Delayed / Incidence not known
    lymphopenia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    peripheral neuropathy / Delayed / Incidence not known
    pneumonitis / Delayed / Incidence not known
    infertility / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    cystitis / Delayed / Incidence not known

    Mild

    vomiting / Early / 1.0-10.0
    nausea / Early / 1.0-10.0
    diarrhea / Early / 1.0-10.0
    tremor / Early / 0-1.0
    agitation / Early / 0-1.0
    rash / Early / 0-1.0
    amenorrhea / Delayed / Incidence not known
    azoospermia / Delayed / Incidence not known
    gonadal suppression / Delayed / Incidence not known
    fever / Early / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Abciximab: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Alteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Amlodipine; Celecoxib: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Amobarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Anagrelide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Anticoagulants: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Antithrombin III: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Apixaban: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Argatroban: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Aspirin, ASA; Butalbital; Caffeine: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Aspirin, ASA; Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Azelastine; Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bacillus Calmette-Guerin Vaccine, BCG: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Barbiturates: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Beclomethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Betamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Betrixaban: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Bivalirudin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Budesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Budesonide; Glycopyrrolate; Formoterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Bupivacaine; Meloxicam: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Butabarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Butalbital; Acetaminophen: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Butalbital; Acetaminophen; Caffeine: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Celecoxib: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Celecoxib; Tramadol: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
    Ciclesonide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cilostazol: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Clopidogrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Clozapine: (Major) It is unclear if concurrent use of other drugs known to cause neutropenia (e.g., antineoplastic agents) increases the risk or severity of clozapine-induced neutropenia. Because there is no strong rationale for avoiding clozapine in patients treated with these drugs, consider increased absolute neutrophil count (ANC) monitoring and consult the treating oncologist.
    Corticosteroids: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Cortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Dabigatran: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Daclizumab: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Dalteparin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Danaparoid: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Deflazacort: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Desirudin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Dexamethasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Diclofenac: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diclofenac; Misoprostol: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diflunisal: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Digoxin: (Moderate) Some antineoplastic agents have been reported to decrease the absorption of digoxin tablets due to their adverse effects on the GI mucosa. For the digoxin tablets, there was a significant reduction in the AUC after chemotherapy to 54.4% +/- 35.5% (mean plus/minus SD) of the value before chemotherapy (p = 0.02), whereas for lanoxin capsules there was an insignificant reduction in AUC to 85.1% +/- 42.7% of the value before chemotherapy. It is prudent to closely monitor patients for loss of clinical efficacy of digoxin tablets while they are receiving chemotherapy.
    Diphenhydramine; Ibuprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Diphenhydramine; Naproxen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Dipyridamole: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to drugs that alter immune system activity like antineoplastic drugs. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Edoxaban: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Enoxaparin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Eptifibatide: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Etodolac: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Famotidine; Ibuprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Febuxostat: (Major) Coadministration of febuxostat and cytotoxic antineoplastic agents has not been studied. After antineoplastic therapy, tumor cell breakdown may greatly increase the rate of purine metabolism to uric acid. Febuxostat inhibits uric acid formation, but does not affect xanthine and hypoxanthine formation. An increased renal load of these two uric acid precursors can occur and result in xanthine nephropathy and calculi.
    Fenoprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Filgrastim, G-CSF: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, filgrastim, is contraindicated for use in patients in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Fludrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flunisolide: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Flurbiprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Fluticasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Salmeterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Umeclidinium; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fluticasone; Vilanterol: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Fondaparinux: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Formoterol; Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Heparin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Hydrocodone; Ibuprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Hydrocortisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Ibuprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Oxycodone: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ibuprofen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Indomethacin: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Intranasal Influenza Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Ketoprofen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Ketorolac: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lansoprazole; Naproxen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Lepirudin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Live Vaccines: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Measles/Mumps/Rubella Vaccines, MMR: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Meclofenamate Sodium: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mefenamic Acid: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Meloxicam: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Mephobarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Methohexital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Methylprednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mometasone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Mycophenolate: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Nabumetone: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nanoparticle Albumin-Bound Sirolimus: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Naproxen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Esomeprazole: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Naproxen; Pseudoephedrine: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Nonsteroidal antiinflammatory drugs: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Oxaprozin: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Palifermin: (Moderate) Palifermin should not be administered within 24 hours before, during infusion of, or within 24 hours after administration of antineoplastic agents.
    Penicillamine: (Major) Do not use penicillamine with antineoplastic agents due to the increased risk of developing severe hematologic and renal toxicity.
    Pentobarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Pentosan: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Phenobarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Piroxicam: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Platelet Inhibitors: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Prasugrel: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Prednisolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Prednisone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Primidone: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Reteplase, r-PA: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Rivaroxaban: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Rofecoxib: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Rotavirus Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Rubella Virus Vaccine Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
    Secobarbital: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Sirolimus: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Smallpox Vaccine, Vaccinia Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Streptokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Sulindac: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Sumatriptan; Naproxen: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Tacrolimus: (Minor) Chlorambucil is known to cause myelosuppression, which may lead to neutropenia related side effects. Concurrent use of chlorambucil with other agents which cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Tbo-Filgrastim: (Major) Because antineoplastic agents exert their toxic effects against rapidly growing cells, such as hematopoietic progenitor cells, filgrastim, is contraindicated for use in patients in the period 24 hours before through 24 hours after treatment with cytotoxic chemotherapy.
    Tenecteplase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Thiopental: (Minor) Barbiturates appear to increase the hepatic activation of chlorambucil to its active metabolite than to inactive metabolite. Clinicians should be alert for a potential increase in chlorambucil related activity and/or toxicity.
    Thrombolytic Agents: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Ticagrelor: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Ticlopidine: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Tinzaparin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Tirofiban: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Tolmetin: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Triamcinolone: (Minor) Because systemically administered corticosteroids exhibit immunosuppressive effects when given in high doses and/or for extended periods, additive effects may be seen with other immunosuppressives or antineoplastic agents.
    Tuberculin Purified Protein Derivative, PPD: (Moderate) Immunosuppressives may decrease the immunological response to tuberculin purified protein derivative, PPD. This suppressed reactivity can persist for up to 6 weeks after treatment discontinuation. Consider deferring the skin test until completion of the immunosuppressive therapy.
    Typhoid Vaccine: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Urokinase: (Moderate) An increased risk of bleeding may occur when thrombolytic agents are used following agents that cause clinically significant thrombocytopenia including antineoplastic agents.
    Valdecoxib: (Major) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants, NSAIDs, platelet inhibitors, including aspirin, ASA, strontium-89 chloride, and thrombolytic agents. In addition, large doses of salicylates (>= 3-4 g/day) can cause hypoprothrombinemia, an additional risk factor for bleeding.
    Varicella-Zoster Virus Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.
    Vorapaxar: (Moderate) An additive risk of bleeding may occur when platelet inhibitors are used with agents that cause clinically significant thrombocytopenia including antineoplastic agents, such as chlorambucil.
    Warfarin: (Moderate) Due to the thrombocytopenic effects of chlorambucil, an additive risk of bleeding may be seen in patients receiving concomitant anticoagulants.
    Yellow Fever Vaccine, Live: (Contraindicated) Live virus vaccines should generally not be administered to an immunosuppressed patient. Live virus vaccines may induce the illness they are intended to prevent and are generally contraindicated for use during immunosuppressive treatment. The immune response of the immunocompromised patient to vaccines may be decreased, even despite alternate vaccination schedules or more frequent booster doses. If immunization is necessary, choose an alternative to live vaccination, or, consider a delay or change in the immunization schedule. Practitioners should refer to the most recent CDC guidelines regarding vaccination of patients who are receiving drugs that adversely affect the immune system.

    PREGNANCY AND LACTATION

    Pregnancy

    Chlorambucil may cause fetal harm in administered during pregnancy. Females of reproductive potential should be advised to avoid becoming pregnant while receiving chlorambucil treatment. If this drug is used during pregnancy or if the patient becomes pregnant while receiving chlorambucil, the patient should be apprised of the potential risks to the fetus. Animal studies have demonstrated fetal abnormalities (i.e., urogenital malformations in rats); however, there have been no well-controlled trials in pregnant woman. Unilateral renal agenesis has been observed in 2 cases when the mother received chlorambucil during the first trimester.

    Women should avoid breast-feeding during chlorambucil therapy due to the potential for serious adverse reactions in breastfed infants. It is unknown whether chlorambucil is excreted into breast milk.

    MECHANISM OF ACTION

    Chlorambucil is a bifunctional alkylating agent and exerts its chemotherapeutic effects by substituting alkyl groups for hydrogen ions in a number of organic compounds. DNA-DNA interstrand crosslinking and DNA-protein crosslinking occur, leading to interference in DNA replication, transcription of RNA, and nucleic acid function. Chlorambucil's onset of activity is extremely slow, which probably explains the drug's lack of acute toxicity. The predominant metabolite of chlorambucil, phenylacetic acid mustard, also has antineoplastic properties and may contribute to the cytotoxicity of the drug.

    PHARMACOKINETICS

    Chlorambucil is administered orally. Chlorambucil binds extensively to plasma proteins (99%). Some distribution to adipose tissue does occur, which leads to a depot of drug that slowly leaks out over time and prolongs chlorambucil's myelosuppressive effects. Chlorambucil crosses the placenta and distributes into ascitic fluid. It is unknown if this drug crosses the blood-brain barrier or if it enters breast milk. Metabolism to the active metabolite, phenylacetic acid mustard, occurs in the liver. Chlorambucil and phenylacetic acid undergo hydrolysis to inactive compounds that are extensively eliminated in the urine. Only 1% of a dose is eliminated as active drug. The half-life of chlorambucil is approximately 92 minutes, and the half-life of phenylacetic acid is 145 minutes. The clinical importance of a longer exposure to the active metabolite has not been extensively explored.

    Oral Route

    Chlorambucil is well absorbed after oral administration. The oral bioavailability of chlorambucil ranges from 56—105%. When taken on an empty stomach, bioavailability can be as low as 50%, but when taken with food the bioavailability can be 75%. Peak plasma concentrations are achieved within 1 hour after administration. The active metabolite, phenylacetic acid mustard, achieves a peak concentration in 2—4 hours.