Imuran

— THERAPEUTIC DISORDERS TREATED —
  • Arthritis/rheumatic disorders
  • Organ rejection prophylaxis
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Imuran Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Azathioprine 50mg; scored tabs.

    Pharmacological Class

    Immunosuppressant (antimetabolite).

    How Supplied

    Tabs—100

    How Supplied

    50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “Imuran” and “50” on each tablet; bottle of 100.

    Storage

    Store at 20-25°C (USP Controlled Room Temperature) (68° to 77°F) in a dry place and protect from light.

    Manufacturer

    Sebela Pharmaceuticals Inc.

    Imuran Indications

    Indications

    To reduce signs/symptoms of active rheumatoid arthritis.

    Imuran Dosage and Administration

    Adult

    Initially 1mg/kg per day in 1–2 divided doses. After 6–8 weeks, if needed, increase by 0.5mg/kg per day increments every 4 weeks; max 2.5mg/kg/day. Maintenance: use lowest effective dose; can decrease by 0.5mg/kg/day (approx. 25mg daily) every 4 weeks. May continue use of aspirin, NSAIDs, and/or low dose steroids during therapy. Concomitant allopurinol: reduce azathioprine to ⅓ or ¼ of usual dose.

    Children

    Not established.

    Renal Impairment

    Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of Imuran or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

    Other Modifications

    Patients with TPMT and/or NUDT15 Deficiency

    • Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. 

    Homozygous deficiency in either TPMT or NUDT15

    • Consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency due to the risk of increased toxicity.

    Heterozygous deficiency in TPMT and/or NUDT15 

    • Dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15 due to the risk of increased toxicity. Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions.

    Effect on Sperm in Animals  

    • Imuran has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

    Imuran Contraindications

    Contraindications

    Rheumatoid arthritis: pregnancy; prior treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan, others).

    Imuran Boxed Warnings

    Boxed Warning

    Malignancy.

    Boxed Warning

    Malignancy

    • Chronic immunosuppression with Imuran, a purine antimetabolite increases risk of malignancy in humans. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. Physicians should inform patients of the risk of malignancy with Imuran.

    Imuran Warnings/Precautions

    Warnings/Precautions

    Increased risk of lymphoma, other malignancies (esp. skin). Risk of hepatosplenic T-cell lymphoma in inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). Monitor CBCs with platelets weekly during 1st month, then twice monthly for 2nd and 3rd months, then monthly or more frequently during dose adjustments. Reduce dose or suspend if rapid fall in or persistently low leukocyte count, or other bone marrow depression develops. Consider TPMT or NUDT15 testing in patients with severe myelosuppression; use alternative therapy if homozygous TPMT or NUDT15 deficiency and reduce dose if heterozygous deficiency. Risk of serious infections (eg, bacterial, viral, fungal, protozoal, opportunistic, including reactivation of latent ones). Discontinue if hepatic veno-occlusive disease is suspected. Avoid sun, UV light. Renal impairment: give lower doses. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

    Warnings/Precautions

    Malignancy

    • Increased risk of developing lymphoma and other malignancies, particularly of the skin. As usual for patients with increased risk for skin cancer, limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor.

    Post-transplant

    • Increased risk of malignancy in renal transplant patients, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including Imuran. Maintain immunosuppressive drug therapy at the lowest effective levels.

    Rheumatoid Arthritis

    • The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients, but it is not possible to define the precise risk of malignancy. 

    Inflammatory Bowel Disease

    • The safety and efficacy of Imuran for the treatment of Crohn's disease and ulcerative colitis have not been established. 

    Cytopenias

    • Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with Imuran. Severe bone marrow suppression may also occur. Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. 

    • Monitor complete blood counts, including platelet counts, 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. Delayed hematologic suppression may 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 other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore, the dose should not be increased intentionally to lower the white blood cell count. 

    TPMT or NUDT15 Deficiency

    • Potential increased risk of severe and life-threatening myelotoxicity in patients with thiopurine S-methyl transferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency if receiving conventional doses of Imuran.

    • Consider evaluation for TPMT and NUDT15 deficiency in patients with severe myelosuppression.

    • Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency and reduced dosages in patients with heterozygous deficiency.

    Serious infections

    • Increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal outcomes. 

    Progressive Multifocal Leukoencephalopathy

    • Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. 

    • Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft. 

    Pregnancy Considerations

    Pregnancy Category D

    • Imuran can cause fetal harm when administered to a pregnant woman. Do not give during pregnancy without carefully weighing the risk versus benefit. Whenever possible, avoid use in pregnant patients. This drug should not be used for treating rheumatoid arthritis in pregnant women. 

    • Benefit versus risk must be weighed carefully before use of Imuran in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. 

    • Advise patient of the potential hazard to fetus If used during pregnancy or if the patient becomes pregnant while taking this drug. 

    • Women of childbearing age should be advised to avoid becoming pregnant.

    Nursing Mother Considerations

    The use of Imuran in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

    Pediatric Considerations

    Safety and efficacy of azathioprine in pediatric patients have not been established. 

    Renal Impairment Considerations

    Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of Imuran or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

    Other Considerations for Specific Populations

    Patients with TPMT and/or NUDT15 Deficiency

    • Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. 

    Homozygous deficiency in either TPMT or NUDT15

    • Consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency due to the risk of increased toxicity.

    Heterozygous deficiency in TPMT and/or NUDT15 

    • Dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15 due to the risk of increased toxicity. Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions.

    Effect on Sperm in Animals  

    • Imuran has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

    Imuran Pharmacokinetics

    Absorption

    Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine.

    Distribution

    Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable.

    Metabolism

    Azathioprine is metabolized to 6-mercaptopurine (6-MP). Activation of 6-MP occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites. The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA.

    6-MP undergoes two major inactivation routes. One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The nucleotide diphosphatase (NUDT15) enzyme is involved in conversion of the 6-TGNs to inactive 6-TG monophosphates. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities.

    Elimination

    Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.

    Azathioprine decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine.

    Imuran Interactions

    Interactions

    See Contraindications. Concomitant febuxostat, DMARDs: not recommended. Anemia, leukopenia with ACEIs. Pancytopenia, myelotoxicity with ribavirin. Exaggerated leukopenia with cotrimoxazole. Caution with concomitant aminosalicylates (eg, sulfasalazine, mesalazine, olsalazine). May antagonize warfarin.

    Imuran Adverse Reactions

    Adverse Reactions

    Leukopenia, thrombocytopenia, anemia, GI toxicity, secondary infection, malignancy, hepatotoxicity, rash, alopecia, fever, arthralgias, diarrhea, steatorrhea, others; progressive multifocal leukoencephalopathy (consider reducing dose).

    Imuran Clinical Trials

    See Literature

    Imuran Note

    Not Applicable

    Imuran Patient Counseling

    Patient Counseling

    Inform patients of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. 

    Inform patients of the danger of infection while receiving Imuran and to report signs and symptoms of infection to their physician. 

    Careful dosage instructions should be given to the patient, especially when Imuran is being administered in the presence of impaired renal function or concomitantly with allopurinol. 

    Advise patients of the potential risks of the use of Imuran during pregnancy and during the nursing period. 

    Inform patients of the increased risk of malignancy following therapy with Imuran.

    Imuran Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Azathioprine 50mg; scored tabs.

    Pharmacological Class

    Immunosuppressant (antimetabolite).

    How Supplied

    Tabs—100

    How Supplied

    50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “Imuran” and “50” on each tablet; bottle of 100.

    Storage

    Store at 20-25°C (USP Controlled Room Temperature) (68° to 77°F) in a dry place and protect from light.

    Manufacturer

    Sebela Pharmaceuticals Inc.

    Imuran Indications

    Indications

    Adjunct for the prevention of rejection in renal homotransplantation.

    Imuran Dosage and Administration

    Adult

    Individualize. Initially 3–5mg/kg once daily starting day of, or in some cases 1–3 days before, transplant. Maintenance: may reduce to 1–3mg/kg daily. Concomitant allopurinol: reduce azathioprine to ⅓ or ¼ of usual dose.

    Children

    Not established.

    Renal Impairment

    Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of Imuran or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

    Other Modifications

    Patients with TPMT and/or NUDT15 Deficiency

    • Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. 

    Homozygous deficiency in either TPMT or NUDT15

    • Consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency due to the risk of increased toxicity.

    Heterozygous deficiency in TPMT and/or NUDT15 

    • Dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15 due to the risk of increased toxicity. Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions.

    Effect on Sperm in Animals  

    • Imuran has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

    Imuran Contraindications

    Contraindications

    Rheumatoid arthritis: pregnancy; prior treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan, others).

    Imuran Boxed Warnings

    Boxed Warning

    Malignancy.

    Boxed Warning

    Malignancy

    • Chronic immunosuppression with Imuran, a purine antimetabolite increases risk of malignancy in humans. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. Physicians should inform patients of the risk of malignancy with Imuran.

    Imuran Warnings/Precautions

    Warnings/Precautions

    Increased risk of lymphoma, other malignancies (esp. skin). Risk of hepatosplenic T-cell lymphoma in inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). Monitor CBCs with platelets weekly during 1st month, then twice monthly for 2nd and 3rd months, then monthly or more frequently during dose adjustments. Reduce dose or suspend if rapid fall in or persistently low leukocyte count, or other bone marrow depression develops. Consider TPMT or NUDT15 testing in patients with severe myelosuppression; use alternative therapy if homozygous TPMT or NUDT15 deficiency and reduce dose if heterozygous deficiency. Risk of serious infections (eg, bacterial, viral, fungal, protozoal, opportunistic, including reactivation of latent ones). Discontinue if hepatic veno-occlusive disease is suspected. Avoid sun, UV light. Renal impairment: give lower doses. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

    Warnings/Precautions

    Malignancy

    • Increased risk of developing lymphoma and other malignancies, particularly of the skin. As usual for patients with increased risk for skin cancer, limit exposure to sunlight and ultraviolet light by wearing protective clothing and using a sunscreen with a high protection factor.

    Post-transplant

    • Increased risk of malignancy in renal transplant patients, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including Imuran. Maintain immunosuppressive drug therapy at the lowest effective levels.

    Rheumatoid Arthritis

    • The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients, but it is not possible to define the precise risk of malignancy. 

    Inflammatory Bowel Disease

    • The safety and efficacy of Imuran for the treatment of Crohn's disease and ulcerative colitis have not been established. 

    Cytopenias

    • Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with Imuran. Severe bone marrow suppression may also occur. Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. 

    • Monitor complete blood counts, including platelet counts, 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. Delayed hematologic suppression may 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 other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore, the dose should not be increased intentionally to lower the white blood cell count. 

    TPMT or NUDT15 Deficiency

    • Potential increased risk of severe and life-threatening myelotoxicity in patients with thiopurine S-methyl transferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency if receiving conventional doses of Imuran.

    • Consider evaluation for TPMT and NUDT15 deficiency in patients with severe myelosuppression.

    • Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency and reduced dosages in patients with heterozygous deficiency.

    Serious infections

    • Increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal outcomes. 

    Progressive Multifocal Leukoencephalopathy

    • Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. 

    • Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft. 

    Pregnancy Considerations

    Pregnancy Category D

    • Imuran can cause fetal harm when administered to a pregnant woman. Do not give during pregnancy without carefully weighing the risk versus benefit. Whenever possible, avoid use in pregnant patients. This drug should not be used for treating rheumatoid arthritis in pregnant women. 

    • Benefit versus risk must be weighed carefully before use of Imuran in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. 

    • Advise patient of the potential hazard to fetus If used during pregnancy or if the patient becomes pregnant while taking this drug. 

    • Women of childbearing age should be advised to avoid becoming pregnant.

    Nursing Mother Considerations

    The use of Imuran in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

    Pediatric Considerations

    Safety and efficacy of azathioprine in pediatric patients have not been established. 

    Renal Impairment Considerations

    Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of Imuran or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

    Other Considerations for Specific Populations

    Patients with TPMT and/or NUDT15 Deficiency

    • Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction. 

    Homozygous deficiency in either TPMT or NUDT15

    • Consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency due to the risk of increased toxicity.

    Heterozygous deficiency in TPMT and/or NUDT15 

    • Dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15 due to the risk of increased toxicity. Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions.

    Effect on Sperm in Animals  

    • Imuran has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

    Imuran Pharmacokinetics

    Absorption

    Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35S-azathioprine.

    Distribution

    Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable.

    Metabolism

    Azathioprine is metabolized to 6-mercaptopurine (6-MP). Activation of 6-MP occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites. The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA.

    6-MP undergoes two major inactivation routes. One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The nucleotide diphosphatase (NUDT15) enzyme is involved in conversion of the 6-TGNs to inactive 6-TG monophosphates. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities.

    Elimination

    Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.

    Azathioprine decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine.

    Imuran Interactions

    Interactions

    See Contraindications. Concomitant febuxostat, DMARDs: not recommended. Anemia, leukopenia with ACEIs. Pancytopenia, myelotoxicity with ribavirin. Exaggerated leukopenia with cotrimoxazole. Caution with concomitant aminosalicylates (eg, sulfasalazine, mesalazine, olsalazine). May antagonize warfarin.

    Imuran Adverse Reactions

    Adverse Reactions

    Leukopenia, thrombocytopenia, anemia, GI toxicity, secondary infection, malignancy, hepatotoxicity, rash, alopecia, fever, arthralgias, diarrhea, steatorrhea, others; progressive multifocal leukoencephalopathy (consider reducing dose).

    Imuran Clinical Trials

    See Literature

    Imuran Note

    Not Applicable

    Imuran Patient Counseling

    Patient Counseling

    Inform patients of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. 

    Inform patients of the danger of infection while receiving Imuran and to report signs and symptoms of infection to their physician. 

    Careful dosage instructions should be given to the patient, especially when Imuran is being administered in the presence of impaired renal function or concomitantly with allopurinol. 

    Advise patients of the potential risks of the use of Imuran during pregnancy and during the nursing period. 

    Inform patients of the increased risk of malignancy following therapy with Imuran.

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