IMUREL

Azathioprine is a prodrug of 6-mercaptopurine, first synthesized in by Gertrude Elion, William Lange, and George Hitchings in an attempt to produce a derivative of 6-mercaptopurine with a better therapeutic index. 9, 10, 11 Azathioprine is used to treat inflammatory conditions like rheumatoid arthritis and as an immunosuppressant in the prevention of renal transplant rejection.

Azathiprine was granted

FDA approval on 20 March 1968.

Azathioprine is indicated to treat rheumatoid arthritis and prevent renal transplant rejection.

Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions.

It has a long duration of action as it is given daily, and has a narrow therapeutic index.

Patients should be counselled regarding the risk of malignancies of the skin and lymphomas.

Azathioprine's mechanism of action is not entirely understood but it may be related to inhibition of purine synthesis, along with inhibition of B and T cells. 5 6-thioguanine triphosphate, a metabolite of azathioprine, modulates activation of rac1 when costimulated with CD28, inducing T cell apoptosis.

This may be mediated through rac1's action on mitogen-activated protein kinase, NF-kappaB.

Target Actions Organism U Amidophosphoribosyltransferase inhibitor

Humans U Ras-related C3 botulinum toxin substrate 1 modulator Humans.

Oral azathioprine is well absorbed, with a T max of 1-2h.

Further data regarding the absorption of azathioprine is not readily available. 6, 7.

Data regarding the volume of distribution of azathioprine is not readily available. 6, 7.

Azathioprine is converted to 6-mercaptopurine nonenzymatically. 4 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 4 6-thiosine-5'-monophosphate is metabolized to 6-methylthiosine-5'-monophosphate by thiopurine methyltransferase or 6-thioxanthylic acid by inosine monophosphate dehydrogenase. 4 6-thioxanthylic acid is metabolized by guanosine monophosphate synthetase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 4 6-thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, 6-thioguanine diphosphate and 6-thioguanine triphosphate.

Hover over products below to view reaction partners Azathioprine 6-Mercaptopurine 6-Thiosine 5'-monophosphate 6-thioxanthylic acid 6-thioguanine monophosphate Thioguanine diphosphate Thioguanine triphosphate 6-methylthiosine 5'-monophosphate 6-thioinosine triphosphate 6-methylthioinosine triphosphate 6-methylmercaptopurine 6-thiouric acid.

Azathioprine and mercaptopurine are not detectable in urine after 8 hours.

Further data regarding the route of elimination of azathioprine are not available.

The half life of azathioprine is approximately 5 hours.

Data regarding the clearance of azathioprine is not readily available. 6, 7.

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The oral

LD in mice is 2500 mg/kg and in rats is 400 mg/kg.

Patients experiencing an overdose may present with bone marrow hypoplasia, bleeding, and infection, which may progress to death.

Patients should be treated with supportive and symptomatic treatments. 8 hour hemodialysis may remove 45% of a dose from serum.

Patients receiving immunosuppressants, including azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin.

Physicians should inform patients of the risk of malignancy with azathioprine.

As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Renal transplant patients are known to have an increased risk of malignancy, 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 azathioprine.

Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.

Information is available on the risk of malignancy with the use of azathioprine in rheumatoid arthritis See ADVERSE REACTIONS.

It has not been possible to define the precise risk of malignancy due to azathioprine.

The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients.

However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine.

Inflammatory Bowel Disease Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with azathioprine.

These cases have had a very aggressive disease course and have been fatal.

The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males.

Some of the patients were treated with azathioprine as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis.

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

Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with azathioprine.

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.

It is suggested that patients on azathioprine have 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 Patients with thiopurine S-methyl transferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency may be at an increased risk of severe and life-threatening myelotoxicity if receiving conventional doses of azathioprine.

Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.

In patients with severe myelosuppression, consider evaluation for TPMT and NUDT15 deficiency.

Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency and reduced dosages in patients with heterozygous deficiency See DOSAGE AND ADMINISTRATION.

Serious infections

Patients receiving immunosuppressants, including azathioprine, are at 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 Cases of

JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including azathioprine.

Risk factors for

PML include treatment with immunosuppressant therapies and impairment of immune function.

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.

Azathioprine 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; 1 a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

Azathioprine tablets can cause fetal harm when administered to a pregnant woman.

Azathioprine tablets should not be given during pregnancy without careful weighing of risk versus benefit.

Whenever possible, use of azathioprine tablets in pregnant patients should be avoided.

This drug should not be used for treating rheumatoid arthritis in pregnant women.

Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily).

Abnormalities included skeletal malformations and visceral anomalies.

Postmarketing cases of intrahepatic cholestasis of pregnancy (ICP) have been reported in women treated with azathioprine during pregnancy.

ICP symptoms and evaluated bile acid levels improved following azathioprine discontinuation.

Discontinue azathioprine tablets if

ICP develops in a pregnant woman.

Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine tablets.

In a detailed case report, 4 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy.

At 10 weeks most features were normalized.

DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily.

There have been two published reports of abnormal physical findings.

Williamson and

Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy.

Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus.

The father was on long-term azathioprine therapy.

Benefit versus risk must be weighed carefully before use of azathioprine tablets in patients of reproductive potential.

There are no adequate and well-controlled studies 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 age should be advised to avoid becoming pregnant.

Azathioprine tablets should not be given to patients who have shown hypersensitivity to the drug.

Azathioprine tablets should not be used for treating rheumatoid arthritis in pregnant women.

Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with azathioprine tablets.

The dose of azathioprine tablets required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management.

The initial dose is usually to 5 mg/kg daily, beginning at the time of transplant.

Azathioprine tablets are usually given as a single daily dose on the day of, and in a minority of cases to 3 days before, transplantation.

Dose reduction to maintenance levels of to 3 mg/kg daily is usually possible.

The dose of azathioprine tablets should not be increased to toxic levels because of threatened rejection.

Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.

Azathioprine tablets are usually given on a daily basis.

The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule.

The dose may be increased, beginning at to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory.

Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually to 8; an adequate trial should be a minimum of 12 weeks.

Patients not improved after 12 weeks can be considered refractory.

Azathioprine tablets 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 therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant.

The optimum duration of maintenance azathioprine tablets has not been determined.

Azathioprine tablets can be discontinued abruptly, but delayed effects are possible.

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 Because of the risk of increased toxicity, consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency.

Heterozygous deficiency in

TPMT and/or NUDT15 Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15.

Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions.

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

Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered.

Several guidelines on this subject have been published. 15-21 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

USP, 50 mg are yellow, round, flat, beveled edge tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "59" and other side is plain and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-229-01 STORAGE Store at 20°C to 25°C (68°F to 77°F) in a dry place and protect from light.

Do not use if blister is torn or broken.

Call your doctor for medical advice about side effects.

Azathioprine tablets can cause fetal harm when administered to a pregnant woman.

Azathioprine tablets should not be given during pregnancy without careful weighing of risk versus benefit.

Whenever possible, use of azathioprine tablets in pregnant patients should be avoided.

This drug should not be used for treating rheumatoid arthritis in pregnant women.

Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily).

Abnormalities included skeletal malformations and visceral anomalies.

Postmarketing cases of intrahepatic cholestasis of pregnancy (ICP) have been reported in women treated with azathioprine during pregnancy.

ICP symptoms and evaluated bile acid levels improved following azathioprine discontinuation.

Discontinue azathioprine tablets if

ICP develops in a pregnant woman.

Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine tablets.

In a detailed case report, 4 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy.

At 10 weeks most features were normalized.

DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily.

There have been two published reports of abnormal physical findings.

Williamson and

Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy.

Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus.

The father was on long-term azathioprine therapy.

Benefit versus risk must be weighed carefully before use of azathioprine tablets in patients of reproductive potential.

There are no adequate and well-controlled studies 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 age should be advised to avoid becoming pregnant.

The use of azathioprine tablets 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.

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