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  • CLASSES

    Other Immunosuppressants
    Other Specific Antirheumatics

    BOXED WARNING

    Inflammatory bowel disease, lymphoma, neoplastic disease, requires an experienced clinician, rheumatoid arthritis, sunlight (UV) exposure

    Azathioprine therapy requires an experienced clinician who is familiar with the mutagenic potential and risk of hematological toxicities associated with the drug. Increased susceptibility to neoplastic disease development, particularly of the skin, results from chronic immunosuppression with azathioprine. Patients with rheumatoid arthritis previously treated with alkylating agents such as cyclophosphamide, chlorambucil, or melphalan may have a prohibitive risk of neoplasia if treated with azathioprine; azathioprine is contraindicated for use by such patients. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Inform patients about the malignancy risk, and instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a sunscreen with a high protection factor.

    DEA CLASS

    Rx

    DESCRIPTION

    Immunosuppressive agent; metabolized to 6-mercaptopurine; commonly used in transplant patients but also is useful in RA, lupus nephritis, and psoriatic arthritis.

    COMMON BRAND NAMES

    Azasan, Imuran

    HOW SUPPLIED

    Azasan/Azathioprine/Imuran Oral Tab: 50mg, 75mg, 100mg
    Azathioprine/Azathioprine Sodium Intravenous Inj Pwd F/Sol: 100mg

    DOSAGE & INDICATIONS

    For kidney transplant rejection prophylaxis.
    NOTE: Complete blood counts including platelet counts are advised weekly during the first month of treatment, twice monthly for the second and third months of treatment, then monthly; more frequent monitoring may be necessary if the dose is altered or other therapy changes occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count or if other evidence of bone marrow depression exists. Early drug discontinuation is advisable for patients with abnormal CBC results that do not respond to dose reduction.
    Oral dosage
    Adults

    3 to 5 mg/kg PO once daily beginning on the day of or 1 to 3 days prior to transplantation. Maintenance dosage is 1 to 3 mg/kg PO once daily. This dosage may vary with patient response. Do NOT increase the azathioprine dose to toxic levels because of threatened rejection. Azathioprine discontinuation may be necessary for severe hematologic or other toxicity even if rejection of the homograft may be a consequence of drug withdrawal. According to renal transplant guidelines, an antiproliferative agent such as azathioprine is to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids. Of note, mycophenolate is suggested to be the first-line antiproliferative agent.

    Children† and Adolescents†

    1 to 2 mg/kg/day PO plus tacrolimus and corticosteroids led to a survival free of graft loss in 89.6% and a survival free from rejection in 68.7% of 93 patients 2 years after transplantation, According to renal transplant guidelines, an antiproliferative agent such as azathioprine is to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids. Of note, mycophenolate is suggested to be the first-line antiproliferative agent.

    Intravenous dosage

    NOTE: Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications.

    Adults

    3 to 5 mg/kg IV once daily beginning on the day of or 1 to 3 days prior to transplantation. Maintenance dosage is 1 to 3 mg/kg IV once daily. Patients may be switched to oral therapy as soon as is practical. Do NOT increase the azathioprine dose to toxic levels because of threatened rejection. Azathioprine discontinuation may be necessary for severe hematologic or other toxicity even if rejection of the homograft may be a consequence of drug withdrawal. According to renal transplant guidelines, an antiproliferative agent such as azathioprine is to be used for initial maintenance immunosuppression with a calcineurin inhibitor such as tacrolimus plus or minus corticosteroids. Of note, mycophenolate is suggested to be the first-line antiproliferative agent.

    For the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms.
    NOTE: Consider alternative therapies for patients who have low or absent thiopurine S-methyltransferase (TPMT) activity (see Contraindications). Dosage reduction is recommended in patients with reduced TPMT activity.
    NOTE: Aspirin, nonsteroidal anti-inflammatory drugs, and/or low dose glucocorticoids may be continued during treatment with azathioprine. Use of azathioprine with disease modifying antirheumatic drugs cannot be recommended; combined use has not been studied.
    NOTE: Patients with rheumatoid arthritis previously treated with alkylating agents such as cyclophosphamide, chlorambucil, or melphalan may have a prohibitive risk of neoplasia if treated with azathioprine.
    Oral dosage
    Adults

    Initially, 1 mg/kg/day (50 to 100 mg) PO can be administered as a single dose or in divided doses. If patient response is not satisfactory within 6 to 8 weeks, dosage may be increased by 0.5 mg/kg/day at 4 week-intervals. Maximum daily dose: 2.5 mg/kg/day. An adequate trial should be a minimum of 12 weeks; patients not improved after 12 weeks can be considered refractory. Azathioprine may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities. Maintenance dosage should be reduced by 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant until the minimum effective dose is achieved. The optimum duration of maintenance azathioprine has not been determined. Doses of 1.1 to 3 mg/kg/day have been used in the treatment of RA and have been found equivalent to therapeutic doses of cyclophosphamide.

    For the treatment of serious manifestations of Behcet's syndrome†.
    Oral dosage
    Adults

    Dosages of 1 to 2 mg/kg PO once daily have been recommended.

    For the treatment of refractory Crohn's disease†.
    Oral dosage
    Adults

    A dose of 1.5 to 2 mg/kg/day PO has been shown to have a favorable effect on disease activity, exert a steroid-sparing effect, and decrease the relapse rate. Several months of therapy may be required before a favorable response is observed.

    Children >= 3 years

    A dosage of 2 mg/kg/day PO has been used in a small number of children with refractory disease. Of those who responded to azathioprine (9/12 patients), corticosteroid dosage reduction was possible. The median time to response was 4 months.

    For the treatment of steroid-resistant or steroid-dependent ulcerative colitis†.
    Oral dosage
    Adults

    A dosage of 2 mg/kg/day PO has been shown to be effective in preventing clinical relapse and/or decreasing steroid requirements. Several months of therapy may be required before a favorable response is observed.

    Children >=  3 years

    A dosage of 2 mg/kg/day PO has been used in a small number of children with refractory disease. Of those who responded to azathioprine (7/9 patients), corticosteroid dosage reduction was possible. The median time to response was less than 3 months.

    For the treatment of lupus nephritis†.
    Oral dosage
    Adults

    Doses up to 2 mg/kg/day PO to reduce glucocorticoid requirement or to control clinically active class III, IV, or V disease that is moderate to severe in pregnant patients; 2 mg/kg/day PO +/- low dose daily glucocorticoids is also a recommended option for maintenance therapy of class III/IV disease for those who respond to induction therapy with mycophenolate mofetil (MMF) or cyclophosphamide and for maintenance therapy of class V disease without proliferative changes and with proteinuria greater than 3 g/24 hours who respond to induction therapy with prednisone and mycophenolate. Fewer patients with active class III, IV, or V disease who had a clinical response to induction with either MMF or cyclophosphamide had treatment failure during maintenance therapy with MMF PO 2 g/day (16.4%) as compared with azathioprine 2 mg/kg/day PO recipients (32.4%) (HR, 0.44; 95% CI, 0.25 to 0.77, p = 0.003). Treatment failure was defined as death, end-stage renal disease, doubling of the serum creatinine concentration, renal flare, or rescue therapy need.

    For the treatment of systemic lupus erythematosus (SLE)†.
    Oral dosage
    Adults

    Some clinicians consider azathioprine the preferred cytotoxic agent for treating SLE. Doses range 2—3 mg/kg/day in combination with prednisone, which should be tapered so that after 6 months of therapy with azathioprine, the patient is only receiving alternate day prednisone. Azathioprine is continued indefinitely with attempts to decrease the dose to the lowest clinically effective dose. Doses as low as 50 mg PO once daily may be successful in some patients.

    For the treatment of dermatomyositis† or polymyositis†.
    Oral dosage
    Adults

    2 mg/kg PO once daily in combination with prednisone may decrease long term disability and lower doses of prednisone may be possible.

    For the treatment of Wegener's granulomatosis†.
    Oral dosage
    Adults

    Doses of 2 to 3 mg/kg PO once daily for 12 to 18 months after complete remission have been recommended.

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

    2 mg/kg PO once daily has been recommended.

    For the treatment of myasthenia gravis† in patients who are poorly controlled with cholinesterase inhibitor therapy.
    Oral dosage
    Adults

    The following regimen has been recommended: initially, 50 mg PO once daily for 1 week, then increase gradually to 2 to 3 mg/kg/day PO. Base dosage on total body weight even in obese patients but do not exceed 250 mg/day.

    For remission maintenance of autoimmune hepatitis†.
    Oral dosage
    Adults

    Doses of 1 to 2 mg/kg/day with or without prednisone have been studied. Seventy-two patients ranging in age from 14 to 71 years (median, 47 years) who were in remission while receiving azathioprine 1 mg/kg PO once daily and low doses of oral prednisolone for at least 1 year were treated with a higher dose of azathioprine (e.g., 2 mg/kg/day PO) and prednisolone was gradually tapered. Of the 72 patients, 12 had relapses on azathioprine alone while the other 60 remained in remission for 12 to 128 months (median, 67 months). The dose of azathioprine was reduced in 26 of these patients after 1 year of remission on the higher dose of azathioprine to 1.5 mg/kg/day and then to 1 mg/kg/day.

    For the treatment of idiopathic pulmonary fibrosis†.
    Oral dosage
    Adults

    2 to 3 mg/kg/day PO to a maximum dose of 150 mg/day PO. Dosing should begin at 25 to 50 mg/day PO and increase gradually, by 25-mg increments, every 7 to 14 days until the maximum dose is reached. Guidelines suggest treatment should be in combination with prednisone and continue for a minimum of 6 months. Objective responses may not be noted until the patient has received 3 months of therapy or more. Exact duration of treatment and need for long-term maintenance should be individualized based on clinical response and tolerance to therapy.

    For the treatment of atopic dermatitis†.
    Oral dosage
    Adults and Adolescents >= 16 years

    Limited data suggest 2.5 mg/kg/day PO may be effective for moderate-to-severe atopic dermatitis. In a small (n = 37), randomized, double-blind, placebo-controlled, crossover study, patients with severe atopic dermatitis received azathioprine 2.5 mg/kg PO once daily for 12 weeks, then placebo for 12 weeks, or vice versa. Topical emollients, corticosteroids, with the exception of very potent corticosteroids, and systemic antihistamines were continued. The Six Area, Six Sign Atopic Dermatitis (SASSAD) score decreased by 26% during azathioprine vs. 3% during placebo (p < 0.01). Additionally, patients receiving azathioprine experienced greater improvement in disruption of work and daytime activities vs. placebo. Twelve patients withdrew from the study during treatment with azathioprine (4 due to GI adverse events) compared to 4 during placebo treatment. Two patients experienced leukopenia during azathioprine treatment; however, neither case necessitated withdrawal from the trial. In another trial in patients with moderate to severe disease despite optimum topical therapy (n = 63), azathioprine was dosed based on thiopurine methyltransferase (TPMT) activity to minimize the risk of azathioprine toxicity. Patients with normal range TPMT activity received azathioprine 1 mg/kg/day PO for 4 weeks followed by a maintenance dose of 2.5 mg/kg/day PO for 8 weeks (n = 58). The use of topical emollients and corticosteroids, with the exception of very potent corticosteroids, was allowed. For all patients in the study, the mean SASSAD score was decreased 37% in the azathioprine-treated patients vs. 20% in the placebo-treated patients (95% CI 4.3% to 29%). Seven patients in the azathioprine group withdrew from the study (4 due to nausea) compared to 2 patients in the placebo group.

    Adults and Adolescents >= 16 years with heterozygous range thiopurine methyltransferase (TPMT) activity

    Limited data suggest 1 mg/kg/day PO. In a trial of patients with moderate to severe disease despite optimum topical therapy (n = 63), 5 patients with heterozygous range TPMT activity received 0.5 mg/kg/day PO for 4 weeks followed by a maintenance dose of 1 mg/kg/day PO for 8 weeks. The use of topical emollients and corticosteroids, with the exception of very potent corticosteroids, was allowed. For all patients in the study, the mean SASSAD score was decreased 37% in the azathioprine-treated patients vs. 20% in the placebo-treated patients (95% CI 4.3% to 29%). The response to the lower-dose azathioprine by the 5 patients with heterozygous range TPMT activity was similar to the those in the normal range with none of the 5 developing myelosuppression. In addition, there were significant improvements from baseline in body area affected, pruritus score, participant and investigator-assessed global response and quality of life in the azathioprine group vs. placebo. Seven patients in the azathioprine group withdrew from the study (4 due to nausea) compared to 2 patients in the placebo group.

    For the treatment of psoriasis†.
    NOTE: Azathioprine should generally be reserved for psoriatic patients who have failed multiple other therapies due to the potential for severe adverse effects.
    Oral dosage
    Adults

    Limited data suggest doses of 1.5 to 3 mg/kg/day orally may be effective. The recommended maximum dosage in dermatologic disease 150 mg/day or less orally. The largest study of azathioprine in psoriasis included 29 patients administered doses of 100 to 300 mg/day PO. A greater than 75% improvement was reported in 13 patients and 6 patients exhibited greater than 50% improvement. In a smaller study comprised of mostly treatment-resistant patients, a dose of 2.5 mg/kg/day PO resulted in greater than 25% improvement in 5/10 patients.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    2.5 mg/kg/day PO for RA; 3—5 mg/kg/day PO or IV for kidney transplant rejection prophylaxis.

    Elderly

    2.5 mg/kg/day PO for RA; 3—5 mg/kg/day PO or IV for kidney transplant rejection prophylaxis.

    Adolescents

    Safety and efficacy have not been established. Doses of 1—2 mg/kg/day PO for kidney transplant rejection prophylaxis have been used.

    Children

    Safety and efficacy have not been established. Doses of 1—2 mg/kg/day PO for kidney transplant rejection prophylaxis have been used.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. Promptly discontinue azathioprine if veno-occlusive disease occurs.

    Renal Impairment

    Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available. Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of azathioprine or its metabolites, may be particularly sensitive to azathioprine, and are usually given lower doses.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.
     
    CAUTION: Observe and exercise appropriate precautions for handling, preparing, and administering cytotoxic drugs.

    Oral Administration
    Extemporaneous Compounding-Oral

    An extemporaneous suspension may be prepared by pulverizing 20 Imuran tablets, levigating with distilled water and 5 mL of Cologel, and adding it to a 2:1 simple syrup/cherry syrup mixture to make a total volume of 20 mL. The suspension contains 50 mg/mL of azathioprine and is stable for 8 weeks when stored in the refrigerator.

    Injectable Administration

    Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

    Intravenous Administration

    Reconstitution:
    Reconstitute 100 mg by adding 10 mL of sterile water for injection to the vial to give a concentration of 10 mg/mL The reconstituted solution should be clear and should be used within 24 hours.
     
    Intravenous injection/infusion:
    NOTE: Azathioprine reconstituted solution is only for intravenous administration - the pH is approximately 9.6.
    Inject appropriate dose directly into a vein or further dilute appropriate dose in 0.9% Sodium Chloride or 5% Dextrose for IV infusion. For IV infusion, the dose may be further diluted with sterile saline or dextrose; the final volume depends on time for the infusion, which is usually 30—60 minutes but may be as short as 5 minutes and as long as 8 hours for the daily dose.

    STORAGE

    Generic:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Protect from light
    - Reconstituted product is stable for 24 hours at room temperature
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in carton until time of use
    Azasan:
    - Protect from light
    - Store at controlled room temperature (between 68 and 77 degrees F)
    - Store in a dry place
    Imuran:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Chronic administration of azathioprine or corticosteroids can result in muscle wasting and/or prolonged negative nitrogen balance. If these effects become evident, dosages of the drug should be reduced.

    Black patients, Caucasian patients, thiopurine methyltransferase (TPMT) deficiency

    Use azathioprine cautiously in patients with thiopurine methyltransferase (TPMT) deficiency, as patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from conventional doses of azathioprine. Thiopurine methyltransferase activity correlates inversely with 6-thioguanine nucleotide concentrations in erythrocytes and presumably other hematopoietic tissues since these cells have negligible xanthine oxidase activities, which leaves TPMT methylation as the only inactivation pathway. Thiopurine methyltransferase genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity, but thiopurine methyltransferase testing cannot substitute for complete blood count (CBC) monitoring during azathioprine receipt. Complete blood counts including platelet counts are advised weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Consider either genotyping or phenotyping patients for TPMT, especially in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in patients with abnormal CBC results that do not respond to dose reduction is advisable. Phenotyping and genotyping methods are commercially available. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. Consider alternative therapies for patients who have low or absent TPMT activity (homozygous for nonfunctional alleles). For Caucasian patients and Black patients, 0.3% inherit two TPMT nonfunctional alleles. Nonfunctional alleles are less common in Asians. The most common nonfunctional alleles associated with reduced levels of TPMT activity are TPMT2, TPMT3A, and TPMT3C. Patients with one nonfunctional allele (heterozygous) have intermediate TPMT activity and may also develop toxicity with conventional doses of azathioprine; cautious use is advised. For Caucasian patients and Black patients, approximately 10% of the population inherit one nonfunctional TPMT allele. Dosage reduction is recommended in patients with reduced TPMT activity. Prompt reduction in dosage or temporary withdrawal of azathioprine may be necessary if there is a rapid fall in or persistently low leukocyte count or if other evidence of bone marrow depression exists. Dose reduction or temporary azathioprine withdrawal may result in reversal of these toxicities.

    Bone marrow suppression

    Cautious use of azathioprine in a patient with bone marrow suppression may be advisable. Severe leukopenia, pancytopenia, macrocytic anemia, and thrombocytopenia can occur during azathioprine therapy; severe bone marrow suppression and bleeding may also occur. Leukopenia does not correlate with therapeutic effect of azathioprine; the azathioprine dose should NOT be increased intentionally to lower the white blood cell count. Physicians using azathioprine for their patients should be very familiar with possible hematologic toxicities. Hematologic status should be monitored closely. Complete blood counts including platelet counts are advised weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Instruct patients to promptly report adverse symptoms including unusual bleeding or bruising.

    Intramuscular injections

    Intramuscular injections should not be administered to patients with platelet counts < 50,000/mm3 who are receiving azathioprine. IM injections may cause bleeding, bruising, or hematomas due to thrombocytopenia secondary to azathioprine-induced bone marrow suppression.

    Hepatic disease

    Because of the possibility of hepatotoxicity, hepatic function should be carefully assessed in patients receiving azathioprine, especially in patients with preexisting hepatic disease. Determinations of serum alkaline phosphatase, bilirubin, and aminotransferase concentration should be performed periodically. Azathioprine may need to be discontinued if jaundice occurs. Rarely, hepatic veno-occlusive disease can occur 1—2 years after the administration of the drug and can be life-threatening. Concomitant serious complications associated with this adverse effect include progressive liver failure, jaundice, ascites, progressive chronic liver failure with progressive portal hypertension and esophageal varices, and deterioration leading to death. Because of the poor prognosis of veno-occlusive disease, it is recommended that liver biopsies be performed at the first sign of hepatic dysfunction. The drug should be promptly discontinued if veno-occlusive disease occurs. Hepatotoxicity occurs less commonly in patients treated with the drug for rheumatoid arthritis.

    Inflammatory bowel disease, lymphoma, neoplastic disease, requires an experienced clinician, rheumatoid arthritis, sunlight (UV) exposure

    Azathioprine therapy requires an experienced clinician who is familiar with the mutagenic potential and risk of hematological toxicities associated with the drug. Increased susceptibility to neoplastic disease development, particularly of the skin, results from chronic immunosuppression with azathioprine. Patients with rheumatoid arthritis previously treated with alkylating agents such as cyclophosphamide, chlorambucil, or melphalan may have a prohibitive risk of neoplasia if treated with azathioprine; azathioprine is contraindicated for use by such patients. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Inform patients about the malignancy risk, and instruct patients to limit sunlight (UV) exposure by wearing protective clothing and by using a sunscreen with a high protection factor.

    Renal disease, renal impairment

    Azathioprine can accumulate in patients with renal impairment, possibly causing toxicity. Azathioprine should be used cautiously in patients with any renal disease causing decreased creatinine clearance. In addition, transplanted kidneys can develop tubular necrosis and may not perform adequately immediately after surgery, which increases the chance for drug accumulation and toxicity, necessitating a dosage reduction.

    Pregnancy

    Azathioprine is a FDA pregnancy risk category D drug and is contraindicated for the treatment of rheumatoid arthritis in pregnant women. Positive evidence of human fetal risk exists based on investigational, marketing, or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus in some circumstances/diseases. Do NOT use azathioprine for the treatment of rheumatoid arthritis in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking azathioprine.

    Breast-feeding

    According to the manufacturer, azathioprine or breast-feeding should be discontinued because of the potential for tumorigenicity from azathioprine. The importance of azathioprine to the mother should determine whether to discontinue breast-feeding or discontinue azathioprine therapy. Azathioprine or its metabolites are transferred at low concentrations in breast milk. However, several small studies, including one with a median follow-up of 3.3 years, have not observed any adverse events in infants exposed to azathioprine through breast-feeding. If azathioprine is used by a lactating mother and there is concern for possible adverse effects in the infant, the following additional precautions could be taken: periodically monitor the infant's complete blood count with differential and liver function tests and/or avoiding breast-feeding for 4 to 6 hours after a dose to significantly reduce infant exposure. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    Children, vaccination

    Patients receiving any vaccination during immunosuppressive therapy or in the 2 weeks prior to starting therapy should be considered unimmunized and should be revaccinated at least 3 months after discontinuation of therapy. Those undergoing immunosuppressive therapy should not be exposed to others who have recently received the oral poliovirus vaccine (OPV). Measles-mumps-rubella (MMR) vaccination is not contraindicated for the close contacts of immunocompromised patients, including health care professionals. Passive immunoprophylaxis with immune globulins may be indicated for immunocompromised persons instead of, or in addition to, vaccination. When exposed to a vaccine-preventable disease such as measles, severely immunocompromised children should be considered susceptible regardless of their vaccination history. Safety and efficacy of azathioprine in children have not been established.

    Immunosuppression, infection, progressive multifocal leukoencephalopathy

    Like all patients receiving chronic immunosuppression, azathioprine recipients are at risk for serious infection. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated aggressively. Cases of progressive multifocal leukoencephalopathy (PML) associated with JC virus infection have been observed among immunosuppressed patients treated with azathioprine. Consider a diagnosis of PML in any patient with new-onset neurological manifestations, including, but not limited to, ataxia, progressive weakness or hemiparesis, confusion, apathy, and visual, speech, or behavior changes. Consider a reduction in immunosuppression for patients who develop PML or other infectious complications. Counsel patients receiving azathioprine about the signs and symptoms of infections and avoidance techniques.

    ADVERSE REACTIONS

    Severe

    leukopenia / Delayed / 5.3-16.0
    pancytopenia / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    veno-occlusive disease (VOD) / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    leukoencephalopathy / Delayed / Incidence not known

    Moderate

    secondary malignancy / Delayed / 0.5-2.8
    thrombocytopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    bleeding / Early / Incidence not known
    ascites / Delayed / Incidence not known
    elevated hepatic enzymes / Delayed / Incidence not known
    jaundice / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known
    pneumonitis / Delayed / Incidence not known

    Mild

    infection / Delayed / 0-20.0
    vomiting / Early / 12.0-12.0
    nausea / Early / 12.0-12.0
    diarrhea / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    myalgia / Early / Incidence not known
    steatorrhea / Delayed / Incidence not known
    fever / Early / Incidence not known
    malaise / Early / Incidence not known
    arthralgia / Delayed / Incidence not known
    rash (unspecified) / Early / Incidence not known
    alopecia / Delayed / Incidence not known

    DRUG INTERACTIONS

    Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive, such as azathioprine. A significant toxicity of zidovudine, ZDV is myelosuppression and resulting neutropenia and anemia.
    Abatacept: (Moderate) Concomitant use of immunosuppressives may potentially increase the risk of serious infection in abatacept treated patients. Advise patients taking abatacept to seek immediate medical advice if they develop signs and symptoms suggestive of infection.
    Adalimumab: (Moderate) The safety and efficacy of adalimumab in patients with immunosuppression have not been evaluated. Patients receiving azathioprine along with adalimumab may be at a greater risk of developing an infection.
    Alefacept: (Severe) Patients receiving other immunosuppressives should not receive concurrent therapy with alefacept; there is the possibility of excessive immunosuppression and subsequent risks of infection and other serious side effects. In clinical efficacy trials, concurrent treatment of alefacept with these types of agents did not occur. The duration of the period following treatment with alefacept that is appropriate before starting other immunosuppressive therapy has not been evaluated.
    Allopurinol: (Major) Concomitant use of allopurinol with azathioprine can result in a large increase in azathioprine activity and toxicity (e.g., bone marrow suppression, leukopenia, pancytopenia). The interaction is well-documented (i.e., multiple case reports over the course of decades) and can be potentially life-threatening. The increase in azathioprine activity is due to the ability of allopurinol to inhibit xanthine oxidase-controlled metabolism, thereby decreasing the elimination of azathioprine. When possible, this drug combination should be avoided. If avoidance of cotherapy is not possible, a reduced dosage of azathioprine (e.g., reduce to one-third to one-quarter of the original dose and close hematologic monitoring are required. Further azathioprine dosage reduction or use of an alternative therapy is recommended for patients who have low or absent thiopurine methyltransferase activity, as both the thiopurine methyltransferase and xanthine oxidase pathways are affected.
    Alpha interferons: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Amlodipine; Benazepril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Angiotensin-converting enzyme inhibitors: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    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: (Severe) 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.
    Balsalazide: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
    Basiliximab: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosuppressives.
    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.
    Benazepril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Benazepril; Hydrochlorothiazide, HCTZ: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    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.
    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.
    Captopril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Captopril; Hydrochlorothiazide, HCTZ: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Carbamazepine: (Minor) Azathioprine should be used cautiously in patients receiving carbamazepine, due to the potential for additive bone marrow/hematologic effects.
    Celecoxib: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Certolizumab pegol: (Moderate) The safety and efficacy of certolizumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with certolizumab may be at a greater risk of developing an infection. Many of the serious infections occurred in patients on immunosuppressive therapy who received certolizumab.
    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.
    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.
    Corticotropin, ACTH: (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.
    Cyclophosphamide: (Moderate) Use caution if cyclophosphamide is used concomitantly with azathioprine, as there may be an increased risk of hepatotoxicity (liver necrosis).
    Daclizumab: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression.
    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.
    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: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Diclofenac; Misoprostol: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Diflunisal: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Diphenhydramine; Ibuprofen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Diphenhydramine; Naproxen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Echinacea: (Major) Echinacea possesses immunostimulatory activity and may theoretically reduce the response to immunosuppressant drugs like azathioprine. Although documentation is lacking, coadministration of echinacea with immunosuppressants is not recommended by some resources.
    Efalizumab: (Major) The safety and efficacy of efalizumab in combination with other immunosuppressive agents have not been evaluated. Patients receiving immunosuppressives should not receive concurrent therapy with efalizumab because of the possibility of increased infections and malignancies. The risk is related to the intensity and duration of immunosuppression rather than the specific agents.
    Enalapril, Enalaprilat: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Enalapril; Felodipine: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Enalapril; Hydrochlorothiazide, HCTZ: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Esomeprazole; Naproxen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Etodolac: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Famotidine; Ibuprofen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Febuxostat: (Severe) Although not formally studied, the coadministration of febuxostat and azathioprine is contraindicated. By inhibiting xanthine oxidase, febuxostat inhibits azathioprine metabolism. As a result, the activity and myelosuppressive effects of azathioprine will be enhanced. Azathioprine toxicity can be life-threatening.
    Fenoprofen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    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: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    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.
    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.
    Fosinopril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Fosinopril; Hydrochlorothiazide, HCTZ: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Golimumab: (Moderate) The safety and efficacy of golimumab in patients with immunosuppression have not been evaluated. Patients receiving immunosuppressives along with golimumab may be at a greater risk of developing an infection.
    Hydrochlorothiazide, HCTZ; Lisinopril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Hydrochlorothiazide, HCTZ; Moexipril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Hydrochlorothiazide, HCTZ; Quinapril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Hydrocodone; Ibuprofen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    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: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Ibuprofen; Oxycodone: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Ibuprofen; Pseudoephedrine: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Indomethacin: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Infliximab: (Moderate) Most infliximab recipients who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. The concurrent use of infliximab and immunosuppressants may also contribute to malignancy risk. However, the use of concomitant immunosuppressives such as 6-mercaptopurine, azathioprine, or methotrexate with infliximab appeared to reduce the frequency of antibodies to infliximab. Patients with Crohn's disease receiving immunosuppressives tended to have fewer infusion-related reactions as compared to patients not receiving immunosuppressive therapy. Also, concomitant methotrexate use, for example, may increase infliximab concentrations. Patients who were antibody-positive were more likely to have higher rates of infliximab clearance and reduced efficacy than were patients who were antibody negative. For patients with inflammatory bowel disease especially adolescents and young adults, consider the possibility that there is a higher risk of hepatosplenic T-cell lymphoma with combination therapy versus an observed increased risk of immunogenicity and hypersensitivity reactions with infliximab monotherapy from the clinical trial data.
    Interferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-2b; Ribavirin: (Major) Pancytopenia and bone marrow suppression have been reported to occur within 3 to 7 weeks after concomitant administration of peginterferon alfa-2a / ribavirin and azathioprine. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine and ribavirin is known to inhibit IMDH, thereby leading to the accumulation of the azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP). This metabolite is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). In the limited number of cases reported (n=8), myelotoxicity was reversible within 4 to 6 weeks after withdrawal of this combination of agents and did not recur upon reintroduction of either treatment alone. All drugs should be discontinued if patients experience pancytopenia and peginterferon alfa-2a / ribavirin should NOT be reintroduced with concomitant azathioprine. Patients receiving concomitant ribavirin and azathioprine should have complete blood counts, including platelet counts, monitored weekly for the first month of treatment, twice monthly for the second and third months of treatment, and monthly thereafter. After the third month of treatment, laboratory monitoring may be increased to more than monthly if dosage or other therapy changes are necessary. (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfacon-1: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Interferon Alfa-n3: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Intranasal Influenza Vaccine: (Severe) 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: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Ketorolac: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive, such as azathioprine. A significant toxicity of zidovudine, ZDV is myelosuppression and resulting neutropenia and anemia.
    Lansoprazole; Naproxen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Leflunomide: (Major) Concomitant use of azathioprine with leflunomide may increase the risk for hepatotoxicity. Caution and close monitoring are advised if these drugs are used together.
    Lesinurad; Allopurinol: (Major) Concomitant use of allopurinol with azathioprine can result in a large increase in azathioprine activity and toxicity (e.g., bone marrow suppression, leukopenia, pancytopenia). The interaction is well-documented (i.e., multiple case reports over the course of decades) and can be potentially life-threatening. The increase in azathioprine activity is due to the ability of allopurinol to inhibit xanthine oxidase-controlled metabolism, thereby decreasing the elimination of azathioprine. When possible, this drug combination should be avoided. If avoidance of cotherapy is not possible, a reduced dosage of azathioprine (e.g., reduce to one-third to one-quarter of the original dose and close hematologic monitoring are required. Further azathioprine dosage reduction or use of an alternative therapy is recommended for patients who have low or absent thiopurine methyltransferase activity, as both the thiopurine methyltransferase and xanthine oxidase pathways are affected.
    Lisinopril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Live Vaccines: (Severe) 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: (Severe) 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: (Severe) 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: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Mefenamic Acid: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Meloxicam: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Mercaptopurine, 6-MP: (Severe) Mercaptopurine, 6-MP is an active metabolite of azathioprine. Concurrent usage is, in essence, a duplication of pharmacologic therapy and may lead to overdosage. Co-therapy of azathioprine and 6-MP should be avoided to reduce the risk of a serious potential for drug-induced side effects and toxicity; case reports of severe immunosuppression and bone marrow suppression have occurred, and some of these cases have resulted in hospitalization, sepsis, and even patient mortality.
    Mesalamine, 5-ASA: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
    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.
    Moexipril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    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.
    Muromonab-CD3: (Major) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosuppressives or antineoplastic agents.
    Mycophenolate: (Major) Concomitant use of mycophenolate and azathioprine is not recommended, as both drugs inhibit purine metabolism. Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosuppressant agents (e.g., mycophenolate). Also, the drug combination has not been studied clinically.
    Nabumetone: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Naproxen: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Naproxen; Pseudoephedrine: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Naproxen; Sumatriptan: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Natalizumab: (Major) Natalizumab for Crohn's disease should not be used in combination with immunosuppressants such as azathiorpine because of the potential for increased risk of progressive multifocal leukoencephalopathy and other serious infections. Ordinarily, patients with mulitple sclerosis who are receiving chronic immunosuppressant therapy should not be treated with natalizumab, for similar reasons.
    Nonsteroidal antiinflammatory drugs: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Olsalazine: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
    Oxaprozin: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Peginterferon Alfa-2a: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Peginterferon Alfa-2b: (Moderate) Additive myelosuppressive effects may be seen when alpha interferons are given concurrently with other myelosuppressive agents, such as antineoplastic agents or immunosuppressives.
    Perindopril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Perindopril; Amlodipine: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Piroxicam: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    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.
    Pyrimidine analogs: (Minor) Additive immunosuppressant affects may be seen when azathioprine is coadministered with other immunosuppressives like antineoplastic agents. Patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects.
    Quinapril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Ramipril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Ribavirin: (Major) Pancytopenia and bone marrow suppression have been reported to occur within 3 to 7 weeks after concomitant administration of peginterferon alfa-2a / ribavirin and azathioprine. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine and ribavirin is known to inhibit IMDH, thereby leading to the accumulation of the azathioprine metabolite, 6-methylthioinosine monophosphate (6-MTITP). This metabolite is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). In the limited number of cases reported (n=8), myelotoxicity was reversible within 4 to 6 weeks after withdrawal of this combination of agents and did not recur upon reintroduction of either treatment alone. All drugs should be discontinued if patients experience pancytopenia and peginterferon alfa-2a / ribavirin should NOT be reintroduced with concomitant azathioprine. Patients receiving concomitant ribavirin and azathioprine should have complete blood counts, including platelet counts, monitored weekly for the first month of treatment, twice monthly for the second and third months of treatment, and monthly thereafter. After the third month of treatment, laboratory monitoring may be increased to more than monthly if dosage or other therapy changes are necessary.
    Rilonacept: (Moderate) Patients receiving immunosuppressives along with rilonacept may be at a greater risk of developing an infection.
    Rituximab: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as azathioprine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Rituximab; Hyaluronidase: (Moderate) The concomitant use of rituximab with other disease modifying anti-rheumatic drugs (DMARDs), such as azathioprine, may result in additive immunosuppression and an increased risk of infection. Monitor patients closely for signs or symptoms of infection.
    Rofecoxib: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Rotavirus Vaccine: (Severe) 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: (Severe) 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.
    Sipuleucel-T: (Major) Concomitant use of sipuleucel-T and immunosuppressives should be avoided. Concurrent administration of immunosuppressives with the leukapheresis procedure that occurs prior to sipuleucel-T infusion has not been studied. Sipuleucel-T stimulates the immune system and patients receiving immunosuppressives may have a diminished response to sipuleucel-T. When appropriate, consider discontinuing or reducing the dose of immunosuppressives prior to initiating therapy with sipuleucel-T.
    Sirolimus: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression.
    Smallpox Vaccine, Vaccinia Vaccine: (Severe) 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.
    Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive. Drugs that may affect the production of leukocytes, including sulfamethoxazole; trimethoprim, SMX-TMP, may lead to exaggerated leukopenia, especially in patients who have received a renal transplant.
    Sulfasalazine: (Moderate) 5-aminosalicylates (e.g., sulfasalazine, mesalamine, olsalazine) may interact with azathioprine and increase the risk of azathioprine-related toxicity. The inhibition of thiopurine methyltransferase activity, one of the enzymes responsible for azathioprine metabolism, by 5-aminosalicylates has been described via in vitro and in vivo study. Theoretically, this interaction could result in a higher risk of bone marrow suppression or other azathioprine dose-related side effects. If concurrent therapy cannot be avoided, closely monitor platelet and complete blood cell counts.
    Sulindac: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Tacrolimus: (Minor) Because azathioprine is an immunosuppressant with myelosuppressive actions, additive affects may be seen with other immunosppressives. While therapy is designed to take advantage of this effect, patients may be predisposed to increased immunosuppression and myelosuppression, resulting in an increased risk of infection or other side effects. The risk is typically related to the intensity and duration of immunosuppression
    Tocilizumab: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Patients receiving immunosuppressants, including azathioprine, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections.
    Tofacitinib: (Severe) Do not use tofacitinib in combination with potent immunosuppressants such as azathioprine. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis. Do not use tofacitinib in combination with potent immunosuppressants such as tacrolimus. A risk of added immunosuppression exists when tofacitinib is coadministered with potent immunosuppressives. Combined use of multiple-dose tofacitinib with potent immunosuppressives has not been studied in patients with rheumatoid arthritis.
    Tolmetin: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Trandolapril: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    Trandolapril; Verapamil: (Major) The use of ACE inhibitors in hypertensive patients receiving azathioprine has been reported to induce anemia and severe leukopenia. This combination should be avoided where possible. When concurrent azathioprine and ACE inhibitor therapy is necessary, the patient should be monitored cautiously for potential myelosuppression.
    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.
    Trimethoprim: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive. Drugs that may affect the production of leukocytes, including sulfamethoxazole; trimethoprim, SMX-TMP, may lead to exaggerated leukopenia, especially in patients who have received a renal transplant.
    Typhoid Vaccine: (Severe) 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.
    Valdecoxib: (Moderate) NSAIDs should be used with caution in patients receiving immunosuppressives as they may mask fever, pain, swelling and other signs and symptoms of an infection.
    Varicella-Zoster Virus Vaccine, Live: (Severe) 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.
    Vigabatrin: (Major) Vigabatrin should not be used with other drugs like azathioprine that are associated with serious ophthalmic effects (e.g., retinopathy or glaucoma) unless the benefit of treatment clearly outweighs the risks.
    Vinblastine: (Minor) Concurrent use of vinca alkaloids with other agents that cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Vinca alkaloids: (Minor) Concurrent use of vinca alkaloids with other agents that cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Vincristine Liposomal: (Minor) Concurrent use of vinca alkaloids with other agents that cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Vincristine: (Minor) Concurrent use of vinca alkaloids with other agents that cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Vinorelbine: (Minor) Concurrent use of vinca alkaloids with other agents that cause bone marrow or immune suppression such as immunosuppressives may result in additive effects.
    Warfarin: (Moderate) Azathioprine decreases warfarin serum concentrations and the INR and thus increases warfarin dosage requirements. If azathioprine is discontinued in a patient stabilized on warfarin, an increased risk of bleeding may occur. It is prudent to monitor the INR and response to warfarin prior to azathioprine initiation, frequently following initiation of azathioprine therapy, and again on azathioprine cessation. Adjust warfarin dosage based on INR and clinical response.
    Yellow Fever Vaccine, Live: (Severe) 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.
    Zidovudine, ZDV: (Moderate) Azathioprine may interact with other drugs that are myelosuppressive, such as azathioprine. A significant toxicity of zidovudine, ZDV is myelosuppression and resulting neutropenia and anemia.

    PREGNANCY AND LACTATION

    Pregnancy

    Azathioprine is a FDA pregnancy risk category D drug and is contraindicated for the treatment of rheumatoid arthritis in pregnant women. Positive evidence of human fetal risk exists based on investigational, marketing, or human studies, but the potential benefit to the mother may outweigh the potential risks to the fetus in some circumstances/diseases. Do NOT use azathioprine for the treatment of rheumatoid arthritis in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking azathioprine.

    According to the manufacturer, azathioprine or breast-feeding should be discontinued because of the potential for tumorigenicity from azathioprine. The importance of azathioprine to the mother should determine whether to discontinue breast-feeding or discontinue azathioprine therapy. Azathioprine or its metabolites are transferred at low concentrations in breast milk. However, several small studies, including one with a median follow-up of 3.3 years, have not observed any adverse events in infants exposed to azathioprine through breast-feeding. If azathioprine is used by a lactating mother and there is concern for possible adverse effects in the infant, the following additional precautions could be taken: periodically monitor the infant's complete blood count with differential and liver function tests and/or avoiding breast-feeding for 4 to 6 hours after a dose to significantly reduce infant exposure. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Azathioprine decreases the metabolism of purines and may inhibit DNA and RNA synthesis as well. Azathioprine also may integrate into nucleic acids, resulting in chromosome breakage, nucleic acid malfunction, or the synthesis of faulty proteins. The drug may interfere with coenzyme functioning, thereby decreasing cellular metabolism, and may inhibit mitosis.
     
    The immunosuppressive activity of azathioprine is due to its ability to inhibit the delayed hypersensitivity reaction and cellular cytotoxic activity that occur during renal allotransplantation. When used for the prevention of tissue rejection, azathioprine usually is administered in conjunction with local radiation therapy, corticosteroids, and other cytotoxic agents. The drug appears to be most effective during the early period of rejection and will not suppress secondary responses or established transplant rejections. Animal studies suggest that the drug is able to suppress the symptoms and the pathology of autoimmune disease.

    PHARMACOKINETICS

    Azathioprine can be given as an injection but it is most commonly administered as oral tablets.
     
    Azathioprine is metabolized to 6-mercaptopurine (6-MP) in the liver. Both azathioprine and 6-MP are rapidly eliminated from blood; neither azathioprine nor 6-MP is detectable in urine after 8 hours. Blood azathioprine concentrations are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide concentrations in tissues rather than with plasma drug concentrations. 6-MP undergoes 3 metabolic pathways. The first pathway is metabolism by xanthine oxidase to produce an inactive metabolite 6-thiouric acid. The second pathway is metabolism by thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP. The third pathway is metabolism by hypoxanthine-guanine phosphoribosyltransferase and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides. The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-thioguanine nucleotides into DNA. Proportions of metabolites are different in individual patients, which presumably accounts for variable magnitude and duration of drug effects. The metabolites, as well as a small amount of unchanged azathioprine and 6-MP, are excreted in the urine.

    Oral Route

    Azathioprine is well absorbed after oral administration, and both azathioprine and its major metabolite mercaptopurine distribute throughout the body and appear to cross the placenta. Azathioprine and mercaptopurine are about 30% bound to serum proteins.