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AzaTHIOprine

Medically reviewed by Drugs.com. Last updated on Oct 12, 2020.

Pronunciation

(ay za THYE oh preen)

Index Terms

  • Azathioprine Sodium

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection [preservative free]:

Generic: 100 mg (1 ea)

Tablet, Oral:

Azasan: 75 mg, 100 mg [scored]

Imuran: 50 mg [scored]

Generic: 50 mg

Brand Names: U.S.

  • Azasan
  • Imuran

Pharmacologic Category

  • Immunosuppressant Agent

Pharmacology

Azathioprine is an imidazolyl derivative of mercaptopurine; metabolites are incorporated into replicating DNA and halt replication; also block the pathway for purine synthesis (Taylor 2005). The 6-thioguanine nucleotide metabolites appear to mediate the majority of azathioprine's immunosuppressive and toxic effects.

Absorption

Oral: Well absorbed

Metabolism

Hepatic; metabolized to 6-mercaptopurine via glutathione S-transferase (GST) reduction. Further metabolized (in the liver and GI tract) via major pathways: Hypoxanthine guanine phosphoribosyltransferase (to active metabolites: 6-thioguanine-nucleotides, or 6-TGNs), nucleotide diphosphate (NUDT15; converts 6-TGN to inactive 6-TG monophosphates), xanthine oxidase (to inactive metabolite: 6-thiouric acid), and thiopurine methyltransferase (TPMT) (to inactive metabolite: 6-methylmercaptopurine)

Excretion

Urine (primarily as metabolites)

Onset of Action

Immune thrombocytopenia (oral): Initial response: 30 to 90 days; Peak response: 30 to 120 days (Neunert 2011)

Time to Peak

Oral: 1 to 2 hours (including metabolites)

Half-Life Elimination

Azathioprine and mercaptopurine: Variable: ~2 hours (Taylor 2005)

Protein Binding

~30%

Special Populations: Renal Function Impairment

Clearance (azathioprine and metabolites) may be delayed in oliguric patients, particularly in those with tubular necrosis in the immediate post-transplant phase (deceased donor transplant).

Use: Labeled Indications

Kidney transplantation: Adjunctive therapy in prevention of rejection of kidney transplants

Guideline recommendations: While azathioprine is FDA approved for adjunctive therapy in prevention of rejection after kidney transplantation, it is no longer recommended as a first-line agent. The KDIGO clinical practice guidelines for care of kidney transplant recipients recommend a combination of maintenance immunosuppressive medications as maintenance therapy, including a calcineurin inhibitor and an antiproliferative agent (mycophenolate preferred) with or without corticosteroids. Azathioprine is recommended as a second-line antiproliferative agent for prevention of acute rejection (KDIGO [Kasiske 2010]).

Rheumatoid arthritis: Treatment of active rheumatoid arthritis (RA), to reduce signs and symptoms.

Appropriate use: While azathioprine is FDA approved for the treatment of active arthritis, the 2012 and 2015 guideline updates from the American College of Rheumatology for the treatment of rheumatoid arthritis do not include azathioprine due to infrequent use in rheumatoid arthritis and a lack of new data (ACR [Singh 2012]; ACR [Singh 2016]). However, azathioprine may be acceptable in certain situations where methotrexate is contraindicated and other alternatives are unable to be used (Cohen 2019).

Off Label Uses

Crohn disease (management after surgical resection)

Data from a small, prospective, open-label pilot trial and from a meta-analysis support the use of azathioprine as management of Crohn disease after surgical resection and has demonstrated to lower endoscopic and clinical recurrence rates [Armuzzi 2013], [Peyrin-Biroulet 2009]. Data from a randomized, placebo controlled trial suggest the benefit of azathioprine (after resection) may be increased when given in combination with metronidazole [D’Haens 2008].

Based on the American Gastroenterological Association Institute guidelines for the management of Crohn disease after surgical resection, azathioprine is an effective first-line agent for prophylactic therapy in patients who are at higher risk for clinical recurrence following surgical resection.

Crohn disease (remission maintenance or steroid-sparing therapy)

Data from 2 randomized, double-blind, placebo-controlled trials support the use of azathioprine in combination with infliximab to achieve corticosteroid-free remission in the treatment of moderate to severe Crohn disease [Colombel 2010], [Lémann 2006].

Based on the American College of Gastroenterology guideline for the management of Crohn disease in adults, azathioprine in combination with an anti-TNF agent (eg, adalimumab, infliximab) for remission maintenance or reduction of steroid use is effective and recommended in the management of this condition. In addition, these guidelines state that azathioprine is not more effective than placebo to induce short-term symptomatic remission and is not recommended for this use. For moderate to severe or moderate to high risk disease, azathioprine may be used in treatment of active disease or as adjunctive therapy for reducing immunogenicity.

Dermatomyositis/polymyositis (relapsed or refractory) (adjunctive management)

Clinical experience suggests that azathioprine may be of benefit (when added to prednisone) in the adjunctive management of relapsed or refractory dermatomyositis or polymyositis that has been unresponsive to conventional treatment, particularly in situations where methotrexate cannot be used as second-line therapy [Briemberg 2003], [Griger 2017].

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Data from a multicenter, prospective, randomized, open-label study, support the use of azathioprine as adjuvant immunosuppressive therapy for the treatment of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) in patients (without poor prognosis factors) who were refractory to or had relapsed after remission induction with corticosteroids [Ribi 2008].

Erythema multiforme (refractory)

Data from a limited number of patients studied as well as clinical experience suggest that azathioprine may be of benefit in the management of erythema multiforme that is resistant to conventional treatment [Farthing 1995], [Schofield 1993], [Schram 2011].

Heart transplantation, prevention of rejection

Data from a randomized, double-blind, controlled study support the use of azathioprine for prevention of rejection in heart transplant patients who cannot tolerate mycophenolic acid derivatives or who have been taking azathioprine and are clinically stable; this study was limited by utilization of cyclosporine as the calcineurin inhibitor rather than tacrolimus, which is now preferred due to improved outcomes [Kobashigawa 1998]. Azathioprine should be used in combination with other maintenance immunosuppressive agents [ISHLT [Costanzo 2010]].

Hepatitis (autoimmune)

Data from a systematic review of 11 randomized, controlled trials support the use of azathioprine in combination with prednisone for induction and maintenance therapy in the treatment of autoimmune hepatitis [Lamers 2010].

Based on the American Association for the Study of Liver Diseases guidelines for the diagnosis and management of autoimmune hepatitis in adults and children, the use of azathioprine in combination with prednisone is an effective and recommended regimen in the management of this condition [AASLD [Mack 2020]].

Immune thrombocytopenia, chronic

Azathioprine in the management of refractory or relapsed chronic immune thrombocytopenia has been primarily evaluated in noncontrolled settings and demonstrated benefit in up to two-thirds of treated patients[Arnold 2010], [Quiquandon 1990]. In international consensus guidelines, azathioprine is recommended as a second-line therapy option for refractory disease [Provan 2010].

Liver transplantation, prevention of rejection

Data from a retrospective evaluation of 2 small, randomized, controlled trials with short follow-up support the use of azathioprine as an option for maintenance immunosuppression after liver transplantation [Germani 2009]; studies in the evaluation were limited by utilization of cyclosporine as the calcineurin inhibitor rather than tacrolimus, which is now preferred due to improved outcomes. Azathioprine was generally equivalent to mycophenolic acid derivatives in terms of efficacy, but safety profiles differed. Guidelines recommend choosing an immunosuppression regimen based on factors including (but not limited to) the following: comorbidities, side effects, previous experience with various immunosuppressive agents, and likelihood of pregnancy [AASLD [Lucey 2013]].

Lung transplantation, prevention of rejection

Data from 2 small, randomized, controlled trials support the use of azathioprine as an option for maintenance immunosuppression after lung transplantation [McNeil 2006], [Palmer 2001]; both studies are limited by utilization of cyclosporine as the calcineurin inhibitor rather than tacrolimus, which is now preferred due to improved outcomes. The efficacy of azathioprine is generally equivalent to mycophenolic acid derivatives; however, side effect profiles differed. Intolerance of mycophenolic acid derivatives is the primary indication for switching to azathioprine.

Lupus nephritis (maintenance phase)

Evidence-based guidelines suggest that azathioprine is effective as maintenance therapy in pregnant and nonpregnant patients with lupus nephritis. According to the guidelines, azathioprine and mycophenolate are considered equally effective as maintenance therapy in lupus nephritis. In patients who are pregnant or plan to become pregnant, azathioprine is the preferred therapy because mycophenolate is teratogenic [ACR [Hahn 2012]]. However, European League Against Rheumatism and European Renal Association—European Dialysis and Transplant Association guidelines recommend that if mycophenolate is successful in the induction phase of lupus nephritis treatment, it should be used over azathioprine as maintenance therapy [EULAR/ERA-EDTA [Bertsias 2012]].

Myasthenia gravis

Data in a limited number of clinical trials suggest that azathioprine may be beneficial for the treatment of myasthenia gravis when used in combination with glucocorticoids in patients who are not adequately controlled with pyridostigmine [Myasthenia Gravis Study Group 1993], [Palace 1998].

Based on the Myasthenia Gravis Foundation of American consensus-based guidance for the management of myasthenia gravis, azathioprine may be used as an immunosuppressive agent in patients with myasthenia gravis who have not met treatment goals after an adequate trial of pyridostigmine. Azathioprine may be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine [Palace 1998], [Sanders 2016].

Pemphigus vulgaris

Data from 2 small randomized studies support the use of azathioprine (in combination with prednisolone) for the treatment of newly diagnosed pemphigus vulgaris [Chams-Davatchi 2007], [Chams-Davatchi 2013].

Pericarditis, recurrent

Evidence from noncontrolled trials indicates that azathioprine may be effective in preventing recurrences in patients with recurrent pericarditis refractory to conventional therapy. The European Society of Cardiology guidelines on the diagnosis and management of pericardial diseases recommend that intravenous immunoglobulin, anakinra, or azathioprine be considered in cases of infection-negative, corticosteroid-dependent recurrent pericarditis in patients not responsive to colchicine.

Psoriasis (alternative agent)

According to the American Academy of Dermatology guidelines, methotrexate, cyclosporine, and acitretin are considered first-line systemic agents for the treatment of psoriasis, but azathioprine may be an appropriate alternative for certain patients [AAD [Menter 2009]].

Ulcerative colitis (remission induction)

Data from a randomized double-blind, placebo-controlled trial support the use of azathioprine, in combination with infliximab, to achieve corticosteroid-free remission in the remission induction treatment of moderate to severe ulcerative colitis [Panaccione 2014]. Clinical experience also suggests that azathioprine (in combination with infliximab) may be of benefit for remission induction in moderate to severe ulcerative colitis [Danese 2011].

Based on the American College of Gastroenterology guidelines for Ulcerative Colitis in Adults, azathioprine may be used in combination with infliximab for induction of remission in patients with moderate to severely active ulcerative colitis when infliximab is used as induction therapy. According to the guidelines, azathioprine monotherapy is not recommended for remission induction in patients with moderately to severely active ulcerative colitis.

Ulcerative colitis (remission maintenance)

In a meta-analysis of randomized clinical trials evaluating the efficacy of thiopurines (eg, azathioprine) for induction and/or maintenance of ulcerative colitis clinical remission, evidence suggests azathioprine may be of benefit for the maintenance of remission in patients with ulcerative colitis [Gisbert 2009].

Based on the American College of Gastroenterology guidelines for Ulcerative Colitis in Adults, azathioprine may be used for maintenance of remission in patients with previously moderately to severely active ulcerative colitis currently in remission following corticosteroid induction.

Uveitis

Results from retrospective studies demonstrate that azathioprine is generally effective in treating uveitis [Galor 2008], [Pacheco 2008], [Saadoun 2010], [Pasadhika 2009]. However, no controlled clinical trials have been performed. An expert review panel recommends azathioprine as third-line therapy for the treatment of uveitis in adults [Díaz-Llopis 2009].

Contraindications

Hypersensitivity to azathioprine or any component of the formulation; pregnancy (in patients with rheumatoid arthritis [see Pregnancy Considerations]); patients with rheumatoid arthritis and a history of treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan) may have a prohibitive risk of malignancy with azathioprine treatment

Dosing: Adult

Note: Consider testing for thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (nucleotide diphosphatase; NUDT15) deficiency in patients who develop severe bone marrow toxicities (may require dose reduction or discontinuation). Dosage reduction or selection of alternative therapy is recommended in patients with TPMT and/or NUDT15 deficiency.

Crohn disease, management after surgical resection (off-label use): Oral:

Monotherapy: 2 to 2.5 mg/kg/day; begin within 2 to 4 weeks after surgery and continue for 12 to 24 months (Armuzzi 2013; Peyrin-Biroulet 2009).

Combination therapy (in combination with metronidazole): 100 mg daily (<60 kg) or 150 mg daily (≥60 kg) for up to 52 weeks (D'Haens 2008) or 2 mg/kg/day for ~18 months after surgery (De Cruz 2015). Note: The benefit of azathioprine may be increased when given in combination with a 3-month course of metronidazole (D'Haens 2008).

Crohn disease (remission maintenance or steroid-sparing therapy) (off-label use): Oral: 1.5 to 2.5 mg/kg/day in combination with an anti-TNF agent (eg, adalimumab, infliximab) (Colombel 2010; Lémann 2006; Lichtenstein 2018).

Dermatomyositis/polymyositis, adjunctive management (off-label use; based on limited data): Oral: 50 mg/day in conjunction with prednisone; increase by 50 mg/week to total dose of 2 to 3 mg/kg/day (Briemberg 2003); Note: Onset of beneficial effects may take 3 to 6 months; however, may be preferred over methotrexate in patients with pulmonary or hepatic toxicity.

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (off-label use): Oral: 2 mg/kg/day for 6 months (Ribi 2008).

Erythema multiforme, refractory (off-label use; based on limited data): Oral: 100 to 150 mg/day (Farthing 1995; Schofield 1993; Schram 2011).

Heart transplantation, prevention of rejection (alternate therapy) (off-label use): Note: Alternative for patients who cannot tolerate a mycophenolic acid derivative (ISHLT [Costanzo 2010]).

Maintenance: Oral: 1 to 3 mg/kg once daily (usual dose: 50 to 150 mg/day) in combination with an appropriate maintenance immunosuppression regimen (Eisen 2003; Keogh 2004; Kobashigawa 1998). Higher calcineurin inhibitor levels may be preferred in patients on azathioprine compared to mycophenolic acid derivatives.

Hepatitis (autoimmune) (off-label use): Oral: Initial: 50 to 100 mg/day in combination with corticosteroids; usual dose: 50 to 150 mg/day. May increase to 2 mg/kg/day in patients who relapse or do not respond (AASLD [Mack 2020]; Lamers 2010). Most patients who are in complete remission for ≥1 year may continue azathioprine (without corticosteroids) at 2 mg/kg/day for relapse prevention (Johnson 1995).

Immune thrombocytopenia, chronic (refractory or relapsed) (off-label use): Oral: 1 to 2 mg/kg/day; maximum dose: 150 mg/day (Provan 2010). Initial response is observed at 30 to 90 days; may take up to 6 months for peak response (Neunert 2011; Provan 2010).

Kidney transplantation, prevention of rejection (alternative therapy): Note: Azathioprine has largely been replaced by mycophenolic acid derivatives (Lee 2012). If other antiproliferative agents become intolerable, patients may be converted to a maintenance dose of azathioprine (El-Agroudy 2009; Lou 2004; Wüthrich 2000; Zhu 2008).

Initial therapy following transplant: IV, Oral: 2 to 5 mg/kg once (Cristelli 2013; manufacturer labeling).

Maintenance: Oral: 1 to 3 mg/kg (usual dose: 50 to 150 mg/day) once daily or 100 mg once daily (for patients <75 kg) or 150 mg (for patients ≥75 kg) once daily (Remuzzi 2007) or 2 mg/kg/day with dose adjusted based on safety/tolerability (Cristelli 2013).

Pregnant patients: ≤2 mg/kg/day (Hou 2013).

Liver transplantation, prevention of rejection (alternate therapy) (off-label use): Note: Azathioprine has largely been replaced by mycophenolic acid derivatives (Germani 2009; AASLD [Lucey 2013]). If other antiproliferative agents become intolerable, patients may be converted to a maintenance dose of azathioprine.

Maintenance: Oral: 1 to 2 mg/kg once daily (usual dose: 50 to 150 mg/day) either alone or in combination with an appropriate maintenance immunosuppression regimen (Germani 2009).

Lung transplantation, prevention of rejection (alternate therapy) (off-label use): Note: Azathioprine has largely been replaced by mycophenolic acid derivatives. If other antiproliferative agents become intolerable, patients may be converted to a maintenance dose of azathioprine.

Maintenance: Oral: 2 mg/kg once daily (usual dose: 50 to 150 mg/day) in combination with an appropriate maintenance immunosuppression regimen (McNeil 2006; Palmer 2001).

Lupus nephritis, maintenance (off-label use): Oral: Initial: 2 mg/kg/day; may reduce to 1.5 mg/kg/day after 1 month (if proteinuria <1 g/day and serum creatinine stable) (Moroni 2006) or target dose: 2 mg/kg/day (Hahn 2012; Houssiau 2010).

Pregnant patients: ≤2 mg/kg/day (Hahn 2012).

Myasthenia gravis (off-label use): Patients who remain significantly symptomatic on pyridostigmine: Oral: Initial: 50 mg/day; increase by 50 mg increments every 1 to 2 weeks to a target dose of 2.5 to 3 mg/kg/day (Sanders 2016). May be added as monotherapy or in conjunction with glucocorticoids and/or pyridostigmine (Palace 1998; Sanders 2016). Onset of clinical response to azathioprine may take up to 1 year, with a maximum effect not apparent until 1 to 2 years (Saperstein 2004; Sieb 2014). Note: For patients who experience flu-like symptoms when initiating with 50 mg/day, some experts recommend initiating with 25 mg/day and gradually increasing the daily dose by 25 to 50 mg every 2 weeks up to 150 mg/day (Nicolle 2016).

Pemphigus vulgaris (off-label use): Oral: Initial: 2.5 mg/kg/day for 2 months, then reduce to 50 mg/day (in combination with prednisolone) (Chams-Davatchi 2007) or 2.5 mg/kg/day (in combination with prednisolone) (Chams-Davatchi 2013).

Pericarditis, recurrent (off-label use): Oral: 150 mg once daily for 2 to 3 months, then 100 mg once daily to suppress clinical symptoms (Marcolongo 1995).

Psoriasis, alternative agent (off-label use): Oral: Initial: 0.5 mg/kg/day, if no occurrence of cytopenia after 6 to 8 weeks of therapy, may increase by 0.5 mg/kg/day every 4 weeks until response; usual dosage: 75 to 150 mg/day; maximum doses may also be guided by TPMT activity (refer to guidelines for details) (AAD [Menter 2009]).

Rheumatoid arthritis (alternative agent):

Oral: 25 to 50 mg/day initially; after 2 weeks may increase by 50 mg/day (~0.5 mg/kg/day) every 4 weeks to 1.5 mg/kg/day; after 3 months if response is inadequate, a higher target dose of a maximum of 3 mg/kg/day may be needed (Belmont 2019).

Manufacturer’s labeling:

Initial: ~1 mg/kg/day (50 to 100 mg) given once daily or divided twice daily; after 6 to 8 weeks, may increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks.

Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly (monitor for delayed toxicities).

Pregnant patients: ≤2 mg/kg/day (Flint 2016).

IV: Note: IV is indicated only in patients unable to tolerate oral medications (dosing should be transitioned from IV to oral as soon as tolerated):

Manufacturer’s labeling:

Initial: ~1 mg/kg/day (50 to 100 mg) given once daily or divided twice daily; after 6 to 8 weeks, may increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks.

Maintenance dose: Reduce dose by 0.5 mg/kg (~25 mg daily) every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly (monitor for delayed toxicities).

Ulcerative colitis, remission induction (off-label use): Oral: 2.5 mg/kg/day in combination with infliximab (ACG [Rubin 2019]; Danese 2011; Panaccione 2014).

Ulcerative colitis, remission maintenance (off-label use): Oral: 2.5 mg/kg/day (Danese 2011; Gisbert 2009).

Uveitis (off-label use): Oral: 2 to 3 mg/kg/day given either alone or in conjunction with corticosteroids and/or immunosuppressants (Pacheco 2008).

Dosage adjustment for TPMT and/or NUDT15 deficiency:

Clinical Pharmacogenetics Implementation Consortium guidelines (Relling 2019):

Normal TPMT or NUDT15 activity (wild type): No initial dosage adjustment necessary; adjust dose based on condition being treated. Allow 2 weeks after each dosage adjustment to reach steady state.

TPMT intermediate or possible intermediate metabolizer or NUDT15 intermediate or possible intermediate metabolizer: Initiate azathioprine with the dose reduced to 30% to 80% of the usual dose and adjust based on the degree of myelosuppression and condition being treated. Allow 2 to 4 weeks after each dosage adjustment to reach steady state. If the starting dose is already below the normal recommended dose, dose reduction may not be recommended.

TPMT poor metabolizer: When used for nonmalignant conditions, consider alternative (non-thiopurine) immunosuppressant therapy. For malignancy, initiate azathioprine at a drastically reduced dose (reduce the daily dose by 10-fold and reduce the frequency from once daily to 3 times a week). Adjust dose based on the degree of myelosuppression and condition being treated. Allow 4 to 6 weeks after each dosage adjustment to reach steady state.

NUDT15 poor metabolizer: When used for nonmalignant conditions, consider alternative (non-thiopurine) immunosuppressant therapy. For malignancy, initiate azathioprine at a drastically reduced dose (reduce the daily dose by 10-fold). Adjust dose based on the degree of myelosuppression and condition being treated. Allow 4 to 6 weeks after each dosage adjustment to reach steady state.

Manufacturer’s labeling:

Heterozygous deficiency (intermediate activity): Reduced doses are recommended in patients with known heterozygous deficiency of TPMT or NUDT15. Patients who are heterozygous for both TPMT and NUDT15 may require more substantial dosage reduction.

Homozygous deficiency (low or deficient activity): Consider alternative therapies in patients with known homozygous deficiency of TPMT or NUDT15.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Consider testing for thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (nucleotide diphosphatase; NUDT15) deficiency in patients who develop severe bone marrow toxicities (may require dose reduction or discontinuation). Dosage reduction or selection of alternative therapy is recommended in patients with TPMT and/or NUDT15 deficiency. IV dose is equivalent to oral dose (dosing should be transitioned from IV to oral as soon as tolerated).

Hepatitis, autoimmune: Limited data available: Children and Adolescents: Oral: Initial: 1 to 2 mg/kg/dose once daily typically in combination with corticosteroids; usual reported range: 0.5 to 2.5 mg/kg/dose; an open-label outcomes trial that followed 66 children and adolescents reported a final mean dose of 1.67 ± 0.55 mg/kg/day; for maintenance therapy, a lower-dose of 1 to 1.5 mg/kg/day may be effective in some patients (AASLD [Manns 2010]; Della Corte 2012; Sheiko 2017; Vitfell-Pedersen 2012).

Inflammatory bowel disease: Limited data available: Infants, Children, and Adolescents: Oral: 2 to 2.5 mg/kg/dose once daily; may titrate to effect; usual reported range: 1 to 3 mg/kg/dose once daily; reported maximum daily dose: 4 mg/kg/day or 200 mg/day; may take several weeks of therapy to be fully effective (ECCO/ESPGHAN [Ruemmel 2014]; Fuentes 2003; Punati 2008; Riello 2011; Sandhu 2010). Some data suggest that pediatric patients with early-onset disease (≤6 years) may require higher doses to achieve remission (Grossman 2008; Stocco 2017). In one trial, a median dose of 3.51 mg/kg/day (maximum daily dose: 5 mg/kg/day) was reported to induce remission in 62% of patients ≤6 years of age vs 17% of those receiving lower doses (ie, <2 to 3 mg/kg/day study group; median dose: 2.46 mg/kg/day) (Grossman 2008).

Immune thrombocytopenia (ITP), chronic refractory: Limited data available: Children ≥2 years and Adolescents: Oral: Maintenance: 2 to 2.5 mg/kg/day, rounded to the nearest 50 mg (Boruchov 2007).

Lupus nephritis: Limited data available: Children and Adolescents: Oral: 2 to 2.5 mg/kg/dose once daily (Bertsias 2012; Marks 2010); Note: Some data suggest less effective in non-Caucasian pediatric patients; some centers recommend use for primary induction in Caucasian patients with less severe disease (Adams 2006; Marks 2010).

Myasthenia gravis, juvenile: Limited data available: Children and Adolescents: Oral: 1 to 3 mg/kg/dose once daily (Ashraf 2006; Linder 1997); most experience in pediatric patients extrapolated from adult trials; most commonly used in combination with corticosteroids as a steroid-sparing agent; however, azathioprine may be a first choice in patients where corticosteroids are contraindicated (Ciafaloni 2019; Finnis 2011).

Transplantation, solid organ: Limited data available: Infants, Children, and Adolescents: IV, Oral: Initial: 3 to 5 mg/kg/dose once daily, beginning at the time of transplant; maintenance: 1 to 3 mg/kg/dose once daily (Denfield 2010; Ford 2006).

Uveitis, juvenile idiopathic arthritis-associated; acute: Limited data available: Children and Adolescents: Oral: Initial mean dose: 2.4 mg/kg/dose once daily; reported range: 1.4 to 3.2 mg/kg/dose once daily; in a retrospective review of patients with acute uveitis (n=41, ages 1 to 15 years), a mean maintenance 2.1 mg/kg/dose (range: 1 to 2.8 mg/kg/dose) once daily was reported as monotherapy and/or in combination with other immunosuppressive agents; infectious etiology was excluded; the authors recommend doses of <3 mg/kg/day (Goebel 2011).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosage adjustment for TPMT and/or NUDT15 deficiency: Infants, Children, and Adolescents:

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for reduced TPMT activity (Relling 2011; Relling 2013):

Heterozygous deficiency (intermediate activity): Consider initiating azathioprine with a reduced dose of 30% to 70% of the target dose and titrate based on tolerance. Allow 2 to 4 weeks after each dosage adjustment to reach steady state.

Homozygous deficiency (low or deficient activity): Consider alternative agents; if use cannot be avoided, initiate azathioprine at drastically reduced doses (reduce the daily dose by 10-fold and reduce the frequency from once daily to 3 times a week). Adjust doses based on the degree of myelosuppression and condition being treated. Allow 4 to 6 weeks after each dosage adjustment to reach steady state. Azathioprine is likely the cause of myelosuppression.

Homozygous wild type (normal activity): No initial dosage adjustment necessary; adjust doses based on guidelines for the condition being treated. Allow 2 weeks after each dosage adjustment to reach steady state.

Dosage adjustment for toxicity: Limited data is available; based on experience in adult patients the following has been suggested:

Rapid WBC count decrease, persistently low WBC count, or serious infection: Reduce dose or temporarily withhold treatment.

Severe toxicity in renal transplantation: May require discontinuation.

Hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease): Permanently discontinue.

Dosing: Adjustment for Toxicity

Rapid WBC count decrease, persistently low WBC count, or serious infection: Reduce dose or temporarily withhold treatment.

Severe toxicity (hematologic or other) in kidney transplantation: May require discontinuation.

Hepatic sinusoidal obstruction syndrome (SOS; veno-occlusive disease): Permanently discontinue.

Rheumatoid arthritis: Leukopenia and thrombocytopenia: Consider a 50% dose reduction or discontinuation; permanently discontinue for persistent cytopenias (Belmont 2019).

Reconstitution

Injection: Add 10 mL of sterile water for injection, and swirl until solution is clear. May further dilute into NS or D5W for infusion.

Canadian product: Reconstitute with 5 to 10 mL sterile water for injection (adding 5 mL will result in a 10 mg/mL solution). May further dilute in NS for infusion.

Extemporaneously Prepared

A 50 mg/mL oral suspension may be prepared with tablets. Crush one-hundred-twenty 50 mg tablets in a mortar and reduce to a fine powder. Add 40 mL of either cherry syrup (diluted 1:4 with Simple Syrup, USP); a 1:1 mixture of Ora-Sweet and Ora-Plus; or a 1:1 mixture of Ora-Sweet SF and Ora-Plus, and mix to a uniform paste. Mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well", "refrigerate", and "protect from light". Stable for 60 days refrigerated.

Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.8862208

Administration

Oral: Most commonly administered once daily. Administering tablets after meals or in divided doses may decrease adverse GI events.

IV: Infusion is usually administered over 30 to 60 minutes. Infusion time is dependent upon the final volume after dilution. While normally given over 30 to 60 minutes, it may be infused over 5 minutes or over up to 8 hours.

Storage

Injection: Store at 20°C to 25°C (68°F to 77°F). Protect from light. Reconstituted solution should be used within 24 hours.

Tablet: Store at 20°C to 25°C (68°F to 77°F). Protect from light and moisture.

Drug Interactions

5-Aminosalicylic Acid Derivatives: May enhance the myelosuppressive effect of Thiopurine Analogs. 5-Aminosalicylic Acid Derivatives may increase serum concentrations of the active metabolite(s) of Thiopurine Analogs. Specifically, exposure to the active 6-thioguanine nucleotides (6-TGN) may be increased. Monitor therapy

Allopurinol: May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. More specifically, allopurinol may increase mercaptopurine serum concentrations and promote formation of active thioguanine nucleotides. Management: Reduce azathioprine dose to one third to one quarter of the usual dose if used with allopurinol, and monitor closely for systemic toxicity. Further dose reduction or alternative therapies should be considered for patients with low or absent TPMT activity. Consider therapy modification

Angiotensin-Converting Enzyme Inhibitors: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Anti-TNF Agents: May enhance the adverse/toxic effect of Thiopurine Analogs. Specifically, the risk for T-cell non-Hodgkin's lymphoma (including hepatosplenic T-cell lymphoma) may be increased. Monitor therapy

Baricitinib: Immunosuppressants may enhance the immunosuppressive effect of Baricitinib. Management: Use of baricitinib in combination with potent immunosuppressants such as azathioprine or cyclosporine is not recommended. Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted. Consider therapy modification

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Cyclophosphamide: AzaTHIOprine may enhance the hepatotoxic effect of Cyclophosphamide. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Management: Consider avoiding Echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Consider therapy modification

Febuxostat: May increase the serum concentration of AzaTHIOprine. Avoid combination

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Inebilizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

InFLIXimab: May enhance the adverse/toxic effect of AzaTHIOprine. Specifically, the risk for T-cell non-Hodgkin's lymphoma (including hepatosplenic T-cell lymphoma) may be increased. InFLIXimab may increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Monitor therapy

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Mercaptopurine: AzaTHIOprine may enhance the myelosuppressive effect of Mercaptopurine. Avoid combination

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Management: Avoid use of immunosuppressants (including systemic corticosteroids) prior to initiation of nivolumab. Use of immunosuppressants after administration of nivolumab (eg, for immune-related toxicity) is unlikely to affect nivolumab efficacy. Consider therapy modification

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Ozanimod: Immunosuppressants may enhance the immunosuppressive effect of Ozanimod. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy

Ribavirin (Oral Inhalation): May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients extra closely for signs/symptoms of myelosuppression. Consider therapy modification

Ribavirin (Systemic): May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients closely for signs/symptoms of myelosuppression. Consider therapy modification

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Management: Consider avoiding concomitant use of roflumilast and immunosuppressants as recommended by the Canadian product monograph. Inhaled or short-term corticosteroids are unlikely to be problematic. Consider therapy modification

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Sulfamethoxazole: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Talimogene Laherparepvec: Immunosuppressants may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk for disseminated herpetic infection may be increased. Avoid combination

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

Tofacitinib: Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib. Management: Concurrent use with antirheumatic doses of methotrexate or nonbiologic disease modifying antirheumatic drugs (DMARDs) is permitted, and this warning seems particularly focused on more potent immunosuppressants. Consider therapy modification

Trimethoprim: May enhance the myelosuppressive effect of AzaTHIOprine. Monitor therapy

Upadacitinib: Immunosuppressants may enhance the immunosuppressive effect of Upadacitinib. Management: Concomitant use of upadacitinib with potent immunosuppressants is not recommended. Avoid combination

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated less than 2 weeks before starting or during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): AzaTHIOprine may enhance the adverse/toxic effect of Vaccines (Live). AzaTHIOprine may diminish the therapeutic effect of Vaccines (Live). Management: Low-dose azathioprine (3 mg/kg/day or less) is not considered sufficiently immunosuppressive to create vaccine safety concerns and is not a contraindication for administration of zoster vaccine. Higher doses of azathioprine should be avoided. Consider therapy modification

Vitamin K Antagonists (eg, warfarin): AzaTHIOprine may diminish the anticoagulant effect of Vitamin K Antagonists. Monitor therapy

Test Interactions

TPMT phenotyping results may not be accurate following recent blood transfusions.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not always defined; dependent upon dose, duration, indication, and concomitant therapy.

Central nervous system: Malaise

Gastrointestinal: Nausea and vomiting (rheumatoid arthritis: 12%), diarrhea

Hematologic & oncologic: Leukopenia (renal transplant: >50%; rheumatoid arthritis: 28%), neoplasia (renal transplant 3% [other than lymphoma], 0.5% [lymphoma]), thrombocytopenia

Hepatic: Hepatotoxicity, increased serum alkaline phosphatase, increased serum bilirubin, increased serum transaminases

Infection: Increased susceptibility to infection (renal transplant 20%; rheumatoid arthritis <1%; includes bacterial, fungal, protozoal, viral, opportunistic, and reactivation of latent infections)

Neuromuscular & skeletal: Myalgia

Miscellaneous: Fever

<1%, postmarketing and/or case reports: Abdominal pain, acute myelocytic leukemia, alopecia, anemia, arthralgia, bone marrow depression, hemorrhage, hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease), hepatosplenic T-cell lymphomas, hepatotoxicity (idiosyncratic) (Chalasani, 2014), hypersensitivity, hypotension, interstitial pneumonitis (reversible), JC virus infection, macrocytic anemia, malignant lymphoma, malignant neoplasm of skin, negative nitrogen balance, pancreatitis, pancytopenia, progressive multifocal leukoencephalopathy, skin rash, steatorrhea, Sweet's syndrome (acute febrile neutrophilic dermatosis)

ALERT: U.S. Boxed Warning

Malignancy:

Chronic immunosuppression with azathioprine, a purine antimetabolite, increases risk of malignancy in humans. Reports of malignancy include post-transplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Health care providers 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. Inform patients of the risk of malignancy with azathioprine.

Warnings/Precautions

Concerns related to adverse effects:

• GI toxicity: The frequency of GI adverse effects (nausea and vomiting) may be decreased with dividing dose or administering after meals. GI hypersensitivity with severe nausea and vomiting has been reported; diarrhea, rash, fever, malaise, myalgia, hypotension, and liver enzyme abnormalities may also occur. Symptoms usually develop within the first several weeks of treatment and are generally reversible upon discontinuation; may recur upon rechallenge.

• Hematologic toxicity: Dose-related hematologic toxicities (leukopenia, thrombocytopenia, and anemias, including macrocytic anemia and/or pancytopenia) may occur; may be severe and/or delayed. Thiopurine methyltransferase (TPMT) genotyping or phenotyping and nudix hydrolase 15 (nucleotide diphosphate [NUDT15]) genotyping may help to identify patients who are at an increased risk for developing azathioprine toxicity (see "TPMT or NUDT 15 deficiency" below). Myelosuppression may be more severe with kidney transplants undergoing rejection. Monitor CBC with differential and platelets weekly during the first month, then twice a month for 2 months, then monthly (or more frequently if clinically indicated). May require treatment interruption, dose reduction, or selection of alternate therapy. Leukopenia does not correlate with therapeutic effect and the dose should not be increased intentionally to lower the white blood cell count.

• Hepatotoxicity: Hepatotoxicity (transaminase, bilirubin, and/or alkaline phosphatase elevations) may occur, usually in kidney transplant patients. Usually occurs within 6 months of transplant and is normally reversible with discontinuation. Monitor liver function periodically. Rarely, hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported; discontinue if hepatic SOS is suspected.

• Infections: Chronic immunosuppression increases the risk of serious, sometimes fatal, infections (bacterial, viral, fungal, protozoal, and opportunistic), including reactivation of latent infections.

• Malignancy: [US Boxed Warning]: Chronic immunosuppression with azathioprine (a purine antimetabolite), increases the risk of malignancy. Malignancies reported have included post-transplant lymphoma and hepatosplenic T-cell lymphoma (HSTCL) in patients with inflammatory bowel disease. Health care providers using this medication should be very familiar with this risk, as well as with the mutagenic potential to both men and women, and with possible hematologic toxicities. Patients should be informed of the risk for malignancy development. HSTCL is a rare white blood cell cancer that is usually fatal and has predominantly occurred in adolescents and young adults treated for Crohn disease or ulcerative colitis and receiving tumor necrosis factor blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. Most cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents, although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy. Kidney transplant patients are known to be at increased risk for malignancy (eg, skin cancer, lymphoma), the risk is increased with aggressive immunosuppression. Limit sun and ultraviolet light exposure and use appropriate sun protection.

• Progressive multifocal leukoencephalopathy: Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including azathioprine (some cases have been fatal). Risk factors for PML include treatment with immunosuppressants and immune system impairment. Consider a diagnosis of PML in any patient presenting with new-onset neurological manifestations; consultation with a neurologist as clinically indicated may be warranted. Consider decreasing the degree of immunosuppression with respect to the risk of organ rejection in transplant patients.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment.

• Renal impairment: Use with caution in patients with renal impairment; dosage reductions may be necessary.

• TPMT or NUDT15 deficiency: Patients with TPMT or NUDT15 deficiency may be at an increased risk of severe and life-threatening myelotoxicity with conventional azathioprine doses. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. Individuals who are TPMT homozygous or compound heterozygous deficient are at very high risk for severe myelosuppression (Relling 2019). TPMT genotyping or phenotyping and NUDT15 genotyping may assist in identifying patients at risk for developing toxicity. Consider testing for TPMT and NUDT15 deficiency in patients with severe myelosuppression. However, TPMT and NUDT15 testing cannot substitute for monitoring CBC in patients receiving azathioprine. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. The Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for thiopurine dosing based on TPMT and NUDT15 genotypes (Relling 2019) recommend reduced initial doses for TPMT and NUDT15 intermediate (and possible intermediate) metabolizers (with dosage adjustments based on myelosuppression). For TPMT and NUDT15 poor metabolizers, CPIC guidelines recommend considering alternative non-thiopurine agents for nonmalignant conditions and drastically reduced doses if used to treat malignancy. Genetic TPMT deficiency is the primary cause of thiopurine intolerance in Europeans and Africans; NUDT15 risk alleles are associated with a majority of thiopurine intolerance in Asians and are also common in Hispanics (Relling 2019).

Concurrent drug therapy issues:

• Mercaptopurine: Azathioprine is metabolized to mercaptopurine; concomitant use may result in profound myelosuppression and should be avoided.

• Vaccines: Immune response to vaccines may be diminished. Toxicity or adverse reactions to live vaccines may be enhanced (depending on the azathioprine dose).

Other warnings/precautions:

• Discontinuation of therapy: Myasthenia gravis: Abrupt cessation of this or any immunosuppressant, especially in clinically unstable individuals, may result in rapid deterioration of myasthenic symptoms and possibly myasthenic crisis (Melzer 2016).

• Experienced health care provider: [US Boxed Warning]: Should be prescribed by health care providers familiar with the risks, including hematologic toxicities and mutagenic potential.

Monitoring Parameters

CBC with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly thereafter; monitor more frequently with dosage modifications), total bilirubin, liver function tests (every 3 months), CrCl, monitor for signs/symptoms of infection and malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss). Azathioprine has been associated with skin cancer with long-term use after kidney transplantation. Patients taking azathioprine for a prolonged time period should avoid sun exposure and be monitored for skin cancer regularly.

Rheumatoid arthritis: CBC with differential at baseline and every 1 to 2 weeks with dose changes, the every 1 to 3 months thereafter, serum creatinine at baseline, and liver function tests at baseline (American College of Rheumatology [ACR 2002]). After a stable dose is achieved, consider monitoring CBC every 4 to 6 weeks and liver function tests every 6 to 8 weeks during azathioprine treatment (Belmont 2019).

Thiopurine S-methyltransferase (TPMT) genotyping or phenotyping: Consider testing for TPMT deficiency, particularly in patients with abnormally low CBC unresponsive to dose reduction. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity (Relling 2019).

Nudix hydrolase 15 (NUDT15) genotyping: Consider genotyping for NUDT15 deficiency in patients who experience severe bone marrow toxicities or repeated myelosuppressive episodes. NUDT15 genotyping may assist in identifying patients at risk for developing toxicity (Relling 2019).

The American Gastroenterological Association suggests routine TPMT testing (enzymatic or genotype) to guide thiopurine dosing in adult patients initiated on thiopurines. The AGA further suggests reactive thiopurine metabolite monitoring to guide therapy changes in adult patients treated with active inflammatory bowel disease or patients experiencing adverse effects potentially due to thiopurine toxicity (targeted 6-thioguanine level between 230 to 450 pmol/8 x 108 RBCs) (Feuerstein 2017).

Reproductive Considerations

The manufacturer recommends that females of reproductive potential avoid becoming pregnant during treatment. However, additional recommendations are available for use in females and males on azathioprine who are planning a pregnancy.

Azathioprine is an acceptable immunosuppressant for use in kidney transplant recipients planning a pregnancy (EBPG 2002; KDIGO 2009; López 2014). Azathioprine should be substituted for mycophenolate 6 weeks prior to conception. Conception may be considered for females on a stable/low maintenance dose for ≥1 year following transplant (EBPG 2002; López 2014).

Azathioprine is also acceptable for use in females with rheumatoid arthritis (BSR/BHPR [Flint 2016]) and other rheumatic and musculoskeletal diseases who are planning a pregnancy. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]). Females treated with azathioprine for lupus nephritis should continue treatment while planning a pregnancy; conception may be considered after 6 months of inactive disease (EULAR/ERA-EDTA [Bertsias 2012]).

Females with autoimmune hepatitis who are planning pregnancy should continue use of azathioprine prior to conception to decrease the risk of flare and hepatic decompensation; biological remission is recommended for 1 year prior to conception (AASLD [Mack 2020]).

Information related to paternal use of azathioprine is limited. However, available data have not shown azathioprine adversely impacting male fertility or increasing the risk of adverse pregnancy outcomes when used within 3 months prior to conception (Bermas 2019; Mouyis 2019). Azathioprine is acceptable for use in males with rheumatoid arthritis (Flint 2016) and other rheumatic and musculoskeletal diseases (ACR [Sammaritano 2020]) who are planning to father a child.

Pregnancy Risk Factor

D

Pregnancy Considerations

Azathioprine crosses the placenta.

Adverse events, including congenital anomalies, immunosuppression, hematologic toxicities (lymphopenia, pancytopenia), and intrauterine growth retardation have been observed in case reports following maternal use in kidney allograft recipients. Some of these adverse outcomes may be dose-related or a result of maternal disease (ACR [Sammaritano 2020]; EBPG 2002). Adverse pregnancy outcomes may also be associated with a kidney transplant, including preterm delivery and low birth weight in the infant and hypertension and preeclampsia in the mother. Appropriate maternal use of lower risk immunosuppressants may help decrease these risks (KDIGO 2009).

Azathioprine can be continued and should be substituted for mycophenolate in patients who become pregnant following a kidney transplant (EBPG 2002; KDIGO 2009; López 2014). Azathioprine may also be used in some pregnant patients who have had a liver (AASLD [Lucey 2013]), heart (ISHLT [Costanzo 2010]) or uterine (Jones 2019 [limited data]) transplant.

Available guidelines suggest that use of azathioprine is acceptable for the treatment of rheumatoid arthritis in pregnant females (BSR/BHPR [Flint 2016]), although use for this indication is contraindicated by the manufacturer. Azathioprine may also be used in the treatment of lupus nephritis (ACR [Hahn 2012]; EULAR/ERA-EDTA [Bertsias 2012]) and other rheumatic and musculoskeletal diseases (ACR [Sammaritano 2020]) during pregnancy.

Females with inflammatory bowel disease who are on maintenance therapy with azathioprine monotherapy may continue treatment during pregnancy; initiating treatment during pregnancy is not recommended. Combination therapy with azathioprine should be avoided due to increased risk of newborn infection (AGA [Mahadevan 2019]).

Treatment with azathioprine for autoimmune hepatitis should be continued during pregnancy. Because pregnancy may increase the risk of a flare, monitor closely for 6 months' postpartum (AASLD [Mack 2020]). Azathioprine may also be useful for the treatment of immune thrombocytopenia in a pregnant female refractory to preferred agents (Provan 2010). Azathioprine is considered acceptable for the treatment of myasthenia gravis in pregnant patients who are not controlled with or unable to tolerate corticosteroids (Sanders 2016).

The Transplant Pregnancy Registry International (TPR) is a registry that follows pregnancies that occur in maternal transplant recipients or those fathered by male transplant recipients. The TPR encourages reporting of pregnancies following solid organ transplant by contacting them at 1-877-955-6877 or https://www.transplantpregnancyregistry.org.

Patient Education

What is this drug used for?

• It is used after a kidney transplant to keep the body from rejecting the kidney.

• It is used to treat rheumatoid arthritis.

• It may be given to you for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Nausea

• Vomiting

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Infection

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes

• Severe loss of strength and energy

• Bruising

• Bleeding

• Severe dizziness

• Passing out

• Diarrhea

• Muscle pain

• Muscle weakness

• Swollen glands

• Night sweats

• Shortness of breath

• Excessive weight loss

• Mole changes

• Skin growths

• Progressive multifocal leukoencephalopathy like confusion, depression, trouble with memory, behavioral changes, change in strength on one side is greater than the other, trouble speaking, change in balance, or vision changes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.