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Azathioprine: Drug information

Azathioprine: Drug information
(For additional information see "Azathioprine: Patient drug information" and see "Azathioprine: Pediatric drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US 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.

Brand Names: US
  • Azasan;
  • Imuran
Brand Names: Canada
  • APO-AzaTHIOprine;
  • AzaTHIOprine-50;
  • Imuran;
  • NU-AzaTHIOprine [DSC];
  • TEVA-AzaTHIOprine
Pharmacologic Category
  • Immunosuppressant Agent
Dosing: Adult

Note: Severe hematologic toxicity may occur, particularly in patients with thiopurine S-methyltransferase (TPMT) and/or nudix hydrolase 15 (nucleotide diphosphatase; NUDT15) deficiency. Testing for TPMT and/or NUDT15 deficiency may be considered; however, expert opinion differs on the role and timing of such testing (Belmont 2021; CPIC [Relling 2019]; Tantisira 2021; manufacturer’s labeling). In patients without TPMT or NUDT15 deficiency, may initiate treatment with the target dose rather than an upward titration (CPIC [Relling 2019]). In patients with TPMT and/or NUDT15 deficiency, dosage reduction or selection of alternative therapy is recommended (AGA [Feuerstein 2017]; CPIC [Relling 2019]; DPWG 2019); refer to "Dosage adjustment for TPMT and/or NUDT15 deficiency" below. Though testing for TPMT and/or NUDT15 deficiency may aid in selecting starting doses for thiopurine therapy, markers of disease progression and/or myelosuppression should be used to further guide dose adjustments (CPIC [Relling 2019]).

Behçet syndrome

Behçet syndrome (off-label use): Oral: Initial: 50 mg once daily; increase by 50 mg every 4 weeks as tolerated, to goal maintenance dose of 2.5 mg/kg once daily (maximum dose not established); may be given in combination with a glucocorticoid (Girgin 2021; Hatemi 2016; Saadoun 2010; Smith 2021; Yazici 1990).

Bullous pemphigoid

Bullous pemphigoid (adjunctive agent) (off-label use): Oral: Initial: 0.5 mg/kg once daily; titrate as tolerated to goal maintenance dose of 2 to 2.5 mg/kg once daily (maximum dose not established); often given in combination with a glucocorticoid (Beissert 2007; Murrell 2021).

Crohn disease

Crohn disease (off-label use):

Induction of remission (adjunctive agent) or maintenance of remission: Oral: Initial: 50 mg once daily; titrate up to 2.5 mg/kg once daily over ≥12 weeks as indicated and tolerated (ACG [Lichtenstein 2018]; A-Rahim 2021; Colombel 2010; Lémann 2006). Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using lean body weight given the toxicities of azathioprine (A-Rahim 2021). For induction, give in combination with a tumor necrosis factor-alpha inhibitor. Duration is generally ≥1 to 2 years (ACG [Lichtenstein 2018]; Al Hashash 2021; Colombel 2010; Lémann 2006).

Management after surgical resection:

Note: Reserve for patients at high risk of recurrence (eg, <30 years of age, tobacco use, ≥2 surgeries for Crohn disease) (ACG [Lichtenstein 2018]; AGA [Nguyen 2017]; ASCRS [Lightner 2020]; Penner 2021).

Oral: Initial: 50 mg once daily; titrate up to 2 to 2.5 mg/kg once daily over ≥12 weeks as indicated and tolerated (A-Rahim 2021; Armuzzi 2013; De Cruz 2015; López-Sanromán 2017; Peyrin-Biroulet 2009). Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using lean body weight given the toxicities of azathioprine (A-Rahim 2021). Initiate within 2 to 8 weeks of surgery; may give as part of an appropriate combination regimen (eg, with metronidazole for 3 months) (A-Rahim 2021; AGA [Nguyen 2017]; Armuzzi 2013; ASCRS [Lightner 2020]; D’Haens 2008; De Cruz 2015).

Dermatomyositis/polymyositis

Dermatomyositis/polymyositis (adjunctive agent) (off-label use):

Note: Onset of clinical response to azathioprine may take 4 to 6 months or longer (Amato 2003; Dalakas 2003).

Oral: Initial: 50 mg once daily in combination with a glucocorticoid; increase daily dose by 50 mg/week to 1.5 mg/kg/day; if inadequate response at 3 months, may increase up to 2.5 mg/kg/day (Briemberg 2003; Bunch 1981; Huapaya 2019; Targoff 2021); some experts do not exceed 250 mg/day (Targoff 2021). Once remission is achieved and glucocorticoids have been tapered, may consider slow taper at monthly intervals with planned cessation of therapy over ~6 months (Targoff 2021).

Eosinophilic granulomatosis with polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss), maintenance therapy (off-label use):

Note: May also be used as glucocorticoid-sparing therapy for patients with glucocorticoid-dependent disease (Doubelt 2020; King 2021a).

Oral: Initial: 25 to 50 mg once daily; increase by 0.5 mg/kg/day every 4 to 6 weeks as tolerated up to 2 mg/kg once daily (maximum dose: 200 mg/day) (King 2021a; Puéchal 2017; Ribi 2008); usual duration: 12 to 18 months; however, longer maintenance therapy may be needed in patients with multiple relapses (King 2021a).

Granulomatosis with polyangiitis and microscopic polyangiitis, maintenance therapy

Granulomatosis with polyangiitis and microscopic polyangiitis, maintenance therapy (alternative agent) (off-label use): Oral: Initial: 50 mg once daily titrated over several weeks to 2 mg/kg once daily as tolerated (maximum dose: 200 mg/day); usual duration: 12 to 24 months after stable remission is induced (Hiemstra 2010; Jayne 2003; Merkel 2021c; Pagnoux 2008; Puéchal 2017).

Hepatitis, autoimmune

Hepatitis, autoimmune (adjunctive agent) (off-label use):

Note: Not recommended for patients with decompensated cirrhosis, acute severe hepatitis, or acute liver failure (AASLD [Mack 2020]; Lamers 2010).

Oral: Initial: 50 mg once daily in combination with a glucocorticoid; may increase dose up to 2 mg/kg once daily based on response and toxicity (AASLD [Mack 2020]; EASL 2015; Heneghan 2021; Johnson 1995; Stellon 1988); some experts do not exceed 200 mg/day (Heneghan 2021). Once remission has been established and maintained for 18 to 24 months, consider treatment withdrawal (eg, reduce azathioprine dose by 50 mg/day every 3 months as tolerated) (AASLD [Mack 2020]; EASL 2015; Heneghan 2021).

Immune thrombocytopenia, chronic

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 (ASH [Neunert 2011]; Provan 2010).

Interstitial pneumonia/interstitial lung disease

Interstitial pneumonia/interstitial lung disease (adjunctive agent) (off-label use): Oral: Initial: 50 mg once daily; increase daily dose in 50 mg increments every 1 to 4 weeks as tolerated to goal maintenance dose of 1.5 to 3 mg/kg once daily (Belmont 2021; Flaherty 2022; Lake 2021; Oldham 2016; Torrisi 2019); some experts do not exceed 200 mg/day (Flaherty 2022; Lake 2021); generally given in combination with a glucocorticoid (Lake 2021; Torrisi 2019).

Lupus nephritis

Lupus nephritis (alternative agent) (off-label use):

Note: Use for subsequent therapy after initial therapy with another agent (eg, cyclophosphamide or mycophenolate) (Falk 2021).

Oral: Initial: 50 mg once daily; increase daily dose in 50 mg increments (or by 0.5 mg/kg/day) every 4 weeks as tolerated to goal maintenance dose of 2 mg/kg once daily (Belmont 2021; Contreras 2004; Dooley 2011; Hahn 2012; Houssiau 2010); some experts do not exceed 200 mg/day (Falk 2021); generally given in combination with a glucocorticoid. Duration is typically ≥2 years (Contreras 2004; Falk 2021; Hahn 2012).

Myasthenia gravis, chronic immunosuppressive therapy

Myasthenia gravis, chronic immunosuppressive therapy (off-label use):

Note: For use as monotherapy or in combination with glucocorticoids in patients with glucocorticoid-resistant or glucocorticoid-dependent disease (Sanders 2016). Due to delayed onset of clinical response, most often given initially in combination with a glucocorticoid (Palace 1998; Sanders 2016).

Oral: Initial: 50 mg once daily; increase daily dose by 50 mg every 1 to 4 weeks as tolerated to a target dose of 2 to 3 mg/kg once daily; some experts do not exceed 200 mg/day (Bird 2021; Farrugia 2020; Nicolle 2016; Palace 1998; Sanders 2016; Sharshar 2021); more rapid titration has also been described (Heckmann 2011). Onset of clinical response to azathioprine may take up to 1 year; maximum efficacy may not be apparent until 1 to 2 years (Sanders 2016; Saperstein 2004).

Pemphigus vulgaris and pemphigus foliaceus

Pemphigus vulgaris and pemphigus foliaceus (alternative agent) (adjunctive agent) (off-label use): Oral: Initial: 1 mg/kg once daily (patients with normal TPMT activity); increase daily dose in 0.5 mg/kg increments over 2 to 3 weeks as tolerated to goal maintenance dose of 2.5 mg/kg once daily (Beissert 2006; Chams-Davatchi 2007; Chams-Davatchi 2013; Hertl 2022). Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using ideal body weight given the toxicities of azathioprine (Hertl 2022). Administer in combination with a glucocorticoid (Beissert 2006; Chams-Davatchi 2013).

Polyarteritis nodosa

Polyarteritis nodosa (off-label use):

Note: In patients with mild disease, may be used adjunctively as glucocorticoid-sparing therapy or for glucocorticoid-resistant disease; for patients with moderate to severe disease, may be used for remission-maintenance immunosuppression (Merkel 2021a; Ribi 2010).

Oral: Initial: 50 mg once daily; if tolerated after 2 weeks, may increase daily dose by 50 mg (~0.5 mg/kg) at 4-week intervals to goal maintenance dose of 2 mg/kg once daily (maximum dose: 200 mg/day) (Belmont 2021; Puéchal 2017; Ribi 2010).

Rheumatoid arthritis

Rheumatoid arthritis (alternative agent):

Note: Not commonly used; reserve for use in patients unable to tolerate methotrexate and other preferred agents (ACR [Singh 2016a]; Cohen 2021). IV dosing regimens are in the prescribing information, but the IV route is not commonly employed.

Oral: Initial: 25 to 50 mg once daily; if tolerated after 2 weeks, may increase daily dose by 50 mg (~0.5 mg/kg) at 4-week intervals to goal maintenance dose of 1.5 mg/kg once daily; if inadequate response after 3 months, may increase up to 3 mg/kg once daily (Belmont 2021; Cohen 2021; De Silva 1981; Woodland 1981); some experts do not exceed 200 mg/day (Cohen 2021).

Sarcoidosis, pulmonary, steroid-refractory disease

Sarcoidosis, pulmonary, steroid-refractory disease (alternative agent) (off-label use): Oral: Initial: 25 to 50 mg once daily; increase daily dose by 50 mg every 2 to 4 weeks as tolerated to goal maintenance dose of ~2 mg/kg once daily (King 2021b; Müller-Quernheim 1999; Vorselaars 2013); some experts do not exceed 200 mg/day; generally given in combination with a glucocorticoid (King 2021b).

Solid organ transplantation

Solid organ transplantation (alternative agent):

Note: Alternative for patients who cannot tolerate or are not candidates for mycophenolate (AASLD [Lucey 2013]; ISHLT [Costanzo 2010]; KDIGO 2009).

Heart transplantation (off-label use): Oral, IV: 1 to 3 mg/kg once daily as part of an appropriate combination regimen (Eisen 2003; ISHLT [Costanzo 2010]; Keogh 2004; Kobashigawa 1998); some experts do not exceed 200 mg/day (Pham 2021).

Kidney transplantation: Oral, IV: 1 to 2 mg/kg once daily as part of an appropriate combination regimen (Cristelli 2013; Wüthrich 2000); manufacturer’s labeling recommends up to 3 mg/kg once daily; some experts do not exceed 150 mg/day (Remuzzi 2007).

Liver transplantation (off-label use): Oral, IV: 1 to 2 mg/kg once daily as part of an appropriate combination regimen (Calmus 2002; Germani 2009; Wiesner 2001); some experts do not exceed 200 mg/day (Vierling 2021).

Lung transplantation (off-label use): Oral, IV: 1 to 2 mg/kg once daily as part of an appropriate combination regimen (Diamond 2021; McNeil 2006; Palmer 2001; Ross 1998); some experts do not exceed 200 mg/day (Diamond 2021).

Takayasu arteritis

Takayasu arteritis (adjunctive agent) (off-label use): Oral: Initial: 50 mg once daily for 1 week, then titrate over several weeks to goal maintenance dose of 1.5 to 2 mg/kg once daily (EULAR [Hellmich 2020]; Goel 2018; Merkel 2021b; Valsakumar 2003); some experts do not exceed 200 mg/day (Merkel 2021b); give in combination with a glucocorticoid (EULAR [Hellmich 2020]; Valsakumar 2003).

Ulcerative colitis

Ulcerative colitis (adjunctive agent) (alternative agent) (off-label use):

Note: The response to azathioprine may take as long as 3 to 6 months (A-Rahim 2021; Feuerstein 2019).

Oral: Initial: 50 mg once daily; titrate up to 2.5 mg/kg once daily over ≥12 weeks as indicated and tolerated (ACG [Rubin 2019]; A-Rahim 2021; Gisbert 2009; Panaccione 2014). Despite lack of pharmacokinetic data to suggest optimal dosing weight, some experts favor using lean body weight given the toxicities of azathioprine (A-Rahim 2021). Give as part of an appropriate combination regimen (ACG [Rubin 2019]).

Uveitis, noninfectious

Uveitis, noninfectious (alternative agent) (off-label use):

Note: Some experts reserve for use in patients with severe or bilateral disease, active inflammation, or glucocorticoid-resistant or glucocorticoid-dependent disease (Rosenbaum 2021).

Oral: 2 to 3 mg/kg once daily (Pacheco 2008); some experts may use up to 4 mg/kg once daily, however, do not exceed 250 mg/day (Rosenbaum 2021).

Dosage adjustment for TPMT and/or NUDT15 deficiency:

Normal TPMT or NUDT15 activity (wild type): No initial dosage adjustment necessary (may initiate with target dose rather than an upward titration); adjust dose based on markers of disease progression and/or myelosuppression. Allow 2 weeks between each dosage increase to reach steady state (CPIC [Relling 2019]).

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 markers of disease progression and/or myelosuppression. Allow 2 to 4 weeks between each dosage increase to reach steady state (CPIC [Relling 2019]).

TPMT poor metabolizer: When used for nonmalignant conditions, consider alternative (non-thiopurine) immunosuppressant therapy. For malignancy, initiate azathioprine at a drastically reduced dose (10% of the recommended daily dose and reduce the frequency from once daily to 3 times a week). Adjust dose based on markers of disease progression and/or myelosuppression. Allow 4 to 6 weeks between each dosage increase to reach steady state (CPIC [Relling 2019]).

NUDT15 poor metabolizer: When used for nonmalignant conditions, consider alternative (non-thiopurine) immunosuppressant therapy. For malignancy, initiate azathioprine at a drastically reduced dose (10% of the recommended daily dose). Adjust dose based on the markers of disease progression and/or myelosuppression. Allow 4 to 6 weeks between each dosage increase to reach steady state (CPIC [Relling 2019]).

Indeterminant TPMT and NUDT15 activity: If activities of both enzymes are indeterminant (ie, results of genetic testing include a combination of uncertain and/or unknown function alleles), monitor closely for toxicity; may consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If activity of either enzyme is known, follow recommendations above (CPIC [Relling 2019]).

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

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason A. Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Azathioprine, 6-mercaptopurine (metabolic intermediate), and 6-thioguanine nucleotide (active metabolite) are not significantly renally eliminated (Bach 1971; Chan 1990; Odlind 1986). 6-thiouric acid (inactive metabolite) is renally eliminated and may contribute to accumulation of 6-thioguanine nucleotide and toxicity potential (Chan 1989; Chan 1990). Clearance (azathioprine and metabolites) may be delayed in oliguric patients, particularly in those with tubular necrosis in the immediate posttransplant phase (deceased donor transplant). Dose recommendations in patients with known or suspected thiopurine S-methyltransferase (TPMT) and nudix hydrolase 15 (nucleotide diphosphatase; NUDT15) deficiency and kidney impairment have not been established; also see dosage adjustment for TPMT and/or NUDT15 deficiency information in the adult dosing section.

Oral, IV:

Altered kidney function:

CrCl ≥30 mL/minute: Initial: No dosage adjustment necessary (Bach 1971; Nemecek 2019; expert opinion).

CrCl 10 to <30 mL/minute: Initial: Administer 75% to 100% of the usual indication-specific dose. If the initial dose is a dose range then it is recommended to begin with the lowest end of the dose range (eg, if the usual dose is 2 to 3 mg/kg once daily then administering 75% to 100% of 2 mg/kg once daily as an initial dose is recommended) (Golightly 2013; Nemecek 2019; expert opinion).

CrCl <10 mL/minute: Initial: Administer 50% to 100% of the usual indication-specific dose. If the initial dose is a dose range then it is recommended to begin with the lowest end of the dose range (eg, if the usual dose is 2 to 3 mg/kg once daily then administering 50% to 100% of 2 mg/kg once daily as an initial dose is recommended) (Golightly 2013; Nemecek 2019; expert opinion).

Hemodialysis, intermittent (thrice weekly): Dialyzable (45% removed during 8 hours of hemodialysis) (Schusziarra 1976): Initial: Administer 50% to 100% of the indication-specific dose; if the initial dose is a dose range then it is recommended to begin with the lowest end of the dose range (eg, if the usual dose is 2 to 3 mg/kg once daily then administering 50% to 100% of 2 mg/kg once daily as an initial dose is recommended) (Golightly 2013; Nemecek 2019; expert opinion). When scheduled dose falls on a dialysis day, administer after hemodialysis. If not administered after hemodialysis, provide a 50% supplemental dose (Schusziarra 1976; expert opinion).

Peritoneal dialysis: Initial: Administer 50% to 100% of the indication-specific dose. If the initial dose is a dose range then it is recommended to begin with the lowest end of the dose range (eg, if the usual dose is 2 to 3 mg/kg once daily then administering 50% to 100% of 2 mg/kg once daily as an initial dose is recommended) (Nemecek 2019; expert opinion).

CRRT: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted. Close monitoring of response and adverse reactions (eg, hematologic toxicity) due to drug accumulation is important.

Initial: Administer 75% to 100% of the indication-specific dose. If the initial dose is a dose range then it is recommended to begin with the lowest end of the dose range (eg, if the usual dose is 2 to 3 mg/kg once daily then administering 75% to 100% of 2 mg/kg once daily as an initial dose is recommended) (Golightly 2013; Nemecek 2019; expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Appropriate dosing requires consideration of adequate drug concentrations (eg, site of infection) and consideration of initial loading doses. Close monitoring of response and adverse reactions (eg, hematologic toxicity) due to drug accumulation is important.

Initial: Administer 75% to 100% of the indication-specific dose. Administer the dose after PIRRT therapy ends on PIRRT days (expert opinion). If the initial dose is a dose range then it is recommended to begin with the lowest end of the dose range (eg, if the usual dose is 2 to 3 mg/kg once daily then administering 75% to 100% of 2 mg/kg once daily as an initial dose is recommended) (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling.

Dosing: Pediatric

(For additional information see "Azathioprine: Pediatric drug information")

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 [Ruemmele 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 (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.

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: Kidney Impairment: Pediatric

Infants, Children, and Adolescents (Aronoff, 2007):

GFR >50 mL/minute/1.73 m2: No adjustment required.

GFR 10 to 50 mL/minute/1.73 m2: Administer 75% of dose once daily.

GFR <10 mL/minute/1.73 m2: Administer 50% of dose once daily.

Hemodialysis (dialyzable; ~45% removed in 8 hours): Administer 50% of normal dose once daily.

CAPD: Administer 50% of normal dose once daily.

CRRT: Administer 75% of normal dose once daily.

Dosing: Hepatic Impairment: Pediatric

There are no dosage adjustments provided in the manufacturer's labeling.

Dosing: Older Adult

Refer to adult dosing.

Dosing: Adjustment for Toxicity: Adult

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).

Dosage Forms: US

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, 75 mg, 100 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

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

Solution Reconstituted, Injection:

Imuran: 50 mg (5 mL)

Tablet, Oral:

Imuran: 50 mg

Generic: 50 mg

Administration: Adult

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.

Administration: Pediatric

Oral: Administer with food or may administer in divided doses to decrease GI upset.

Parenteral: IV: May administer over 5 minutes at a concentration not to exceed 10 mg/mL; or may infuse as diluted solution (<10 mg/mL) over 30 to 60 minutes or longer (eg, 8 hours) dependent upon final volume and specific protocols.

Hazardous Drugs Handling Considerations

Hazardous agent (NIOSH 2016 [group 2]).

Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).

Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.

Use: Labeled Indications

Kidney transplantation, prevention of rejection:

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 Kidney Disease Improving Global Outcomes (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 2009).

Rheumatoid arthritis: Treatment of active rheumatoid arthritis, 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 2016a]). However, azathioprine may be acceptable in certain situations where methotrexate is contraindicated and other alternatives are unable to be used (Cohen 2021).

Use: Off-Label: Adult

Behçet syndrome; Bullous pemphigoid; Crohn disease; Dermatomyositis/polymyositis; Eosinophilic granulomatosis with polyangiitis (Churg-Strauss); Granulomatosis with polyangiitis and microscopic polyangiitis; Heart transplantation, prevention of rejection; Hepatitis, autoimmune; Immune thrombocytopenia, refractory; Interstitial pneumonia/interstitial lung disease; Liver transplantation, prevention of rejection; Lung transplantation, prevention of rejection; Lupus nephritis; Myasthenia gravis, chronic immunosuppressive therapy; Pemphigus vulgaris and pemphigus foliaceus; Polyarteritis nodosa; Sarcoidosis, pulmonary, steroid-refractory disease; Takayasu arteritis; Ulcerative colitis; Uveitis, noninfectious

Medication Safety Issues
Sound-alike/look-alike issues:

AzaTHIOprine may be confused with azaCITIDine, azidothymidine, azithromycin, Azulfidine.

Imuran may be confused with Elmiron, Enduron, Imdur, Inderal, Tenormin.

High alert medication:

This medication is in a class the Institute for Safe Medication Practices (ISMP) includes among its list of drug classes that have a heightened risk of causing significant patient harm when used in error.

Other safety concerns:

Azathioprine is metabolized to mercaptopurine; concurrent use of these commercially-available products has resulted in profound myelosuppression.

Adverse Reactions (Significant): Considerations
GI effects

Use of azathioprine may result in dose-related GI intolerance including nausea, vomiting, and diarrhea. Symptoms are generally reversible upon discontinuation or with dosage reduction (Ref). GI adverse effects may result in treatment discontinuation (Ref).

An immune-mediated GI reaction characterized by severe nausea and vomiting has been rarely reported (Ref); additional symptoms may include diarrhea, skin rash, fever, malaise, myalgia, hypotension, and liver enzyme abnormalities. Reaction may recur upon rechallenge (Ref).

Mechanism:

GI intolerance: Dose-related; related to the pharmacologic action (Ref). Azathioprine is metabolized to 6-mercaptopurine (6-MP) which can then be converted into the active 6-thioguanine nucleotide (6-TGN) and thioguanine triphosphate (TGTP) metabolites. The cytotoxic actions of 6-MP are at least partly due to the incorporation of 6-TGN into DNA during therapy (Ref). Because thiopurine methyltransferase (TPMT) catalyzes the inactivation of 6-MP, decreased activity of TPMT may result in a higher risk of azathioprine-induced GI effects (Ref).

GI hypersensitivity: Immune-mediated; may be IgE-mediated (type 1) (Ref).

Onset: Varied; symptoms typically develop within the first several weeks of treatment. However, late onset (≥5 months of therapy) has also been described (Labidi 2020; Qiu 2015). Although there is limited evidence that the immune-mediated reaction is a type 1 reaction, onset is not immediate and the reaction may take months to develop (Riedel 1990).

Risk factors:

• Higher doses; Note: Risk may be reduced with divided doses or administration after meals.

• TPMT homozygous or compound heterozygous deficient allele carriers (Ref).

• Females (Ref)

• Crohn disease (Ref)

Hematologic toxicity

Use of azathioprine may result in reversible, dose-related hematologic toxicities (eg, leukopenia, thrombocytopenia, and anemias, including macrocytic anemia and/or pancytopenia); death associated with pancytopenia has been reported in patients with absent thiopurine methyltransferase (TPMT) activity. Clinicians should note that severe and life-threatening myelotoxicity may occur even at conventional doses in patients with TPMT or nudix hydrolase 15 (nucleotide diphosphate [NUDT15]) deficiency. Hematologic toxicity may require treatment interruption, dose reduction, or selection of alternate therapy.

Mechanism: Dose-related; related to the pharmacologic action. Azathioprine is metabolized to 6-mercaptopurine (6-MP) which can then be converted into the active 6-thioguanine nucleotide (6-TGN) and thioguanine triphosphate (TGTP) metabolites. The cytotoxic actions of 6-MP are at least partly due to the incorporation of 6-TGN and TGTP into DNA during therapy (Ref). Because TPMT and NUDT15 catalyzes the inactivation of 6-MP and TGTP, respectively, decreased activity of TPMT and/or NUDT15 results in a higher risk of azathioprine-induced myelotoxicity (Ref).

Onset: Delayed; most often occurs early (eg, within 3 to 6 months of treatment initiation) but may also occur months or years later (Ref). Timing of onset may differ depending on genotype (Ref).

Risk factors:

• Reduced TPMT and/or NUDT15 activity (Ref); TPMT and/or NUDT15 poor metabolizers (homozygous or compound heterozygous deficiency) are at very high risk for severe myelosuppression (Ref)

- Genetic TPMT deficiency is the primary cause of thiopurine intolerance in patients from Europe and Africa (Ref)

- NUDT15 risk alleles are associated with a majority of thiopurine intolerance in patients from East Asia and are also common in Hispanic patients (Ref)

• Concomitant use of other myelosuppressive agents (such as those used to treat rejection)

• Concomitant use of agents that may increase the concentration of cytotoxic metabolites including xanthine oxidase inhibitors (eg, allopurinol, febuxostat) and ribavirin

• Concomitant use of angiotensin-converting enzyme inhibitors (eg, lisinopril) and loop diuretics

Infections

Azathioprine is an immunosuppressant; therefore, use may result in bacterial infections, viral infections, fungal infections, protozoal infections, and opportunistic infections, including reactivation of latent infections. Infections may be severe and potentially fatal. As the degree of immunosuppression increases (due to use of additional immunosuppressant agents, preexisting immunosuppression, etc), the risk of infectious complications will increase. The risk of infection with azathioprine as compared to other immunosuppressants also differs based on multiple factors including concomitant immunosuppressant regimen and disease state (Ref).

Viral infections reported with the use of azathioprine include JC virus infection resulting in progressive multifocal leukoencephalopathy, cytomegalovirus (CMV) disease, herpes simplex virus infection, human papillomavirus infection, and reactivation of hepatitis B and tuberculosis (Ref).

Mechanism: Exact mechanism unknown; related to pharmacologic action. Azathioprine metabolites are incorporated into replicating DNA and halt replication; also blocks the pathway for purine synthesis (Ref). Azathioprine and its metabolites may also be a direct inhibitor of cytotoxic T cell and natural killer cell function (Ref).

Onset: Varied; in general, the onset of infections following solid organ transplant varies greatly; the majority of clinically important infections occur within the first 180 days (Ref).

Risk factors:

• Concomitant use of other immunosuppressive agents or preexisting immune function impairment

CMV infection: Transplant recipients that are CMV seronegative at the time of transplant who receive a graft from a CMV seropositive donor (Ref)

Liver dysfunction

Cholestatic, hepatocellular, or mixed type hepatotoxicity may occur (Ref). Hepatic effects most often occur in transplant patients and symptoms are normally reversible with discontinuation (Ref). Patients may experience transient transaminase elevations without associated symptoms or clinically significant hepatotoxicity (Ref). In patients who develop cholestatic hepatitis, serum alkaline phosphatase concentrations may be low or even normal at the onset of jaundice (Ref). Rarely, hepatic sinusoidal obstruction syndrome (SOS; formerly called veno-occlusive disease [VOD]) has been reported (Ref). Patients who develop hepatoxicity may require treatment interruption, dose reduction, or selection of alternate therapy.

An immune-mediated reaction resulting in moderate-to-severe liver enzyme abnormalities as well as fever, rash, chills, nausea, and diarrhea suggestive of cholestasis has been rarely reported (Ref). Reaction may recur upon rechallenge (Ref).

Mechanism: Multiple mechanisms exist; hepatotoxicity may be characterized as cholestatic, hepatocellular, or mixed type and/or a result of an immune-mediated reaction (Ref). Azathioprine is metabolized to 6-mercaptopurine (6-MP) which can then be converted into the active 6-thioguanine nucleotide (6-TGN) and methylated metabolites (MeMP), including 6-methylmercaptopurine ribonucleotides (6-MMPR). Both 6-TGN and MeMP may cause hepatic damage due to inhibition of purine de novo synthesis (Ref).

Onset: Varied; hepatotoxicity usually occurs within 6 months of treatment initiation or dose escalation (Ref). Early onset (within days of treatment initiation) as well as late onset (years after treatment initiation) have also been reported (Ref). Immune-mediated hepatotoxicity has occurred within 2 weeks of treatment initiation (Ref).

Risk factors:

• Transplant recipients

• Elevated 6-MMPR concentration (>5,700 pmol/8 x 108 erythrocytes) (Ref)

• May be more common in males (Ref); however, some studies have shown females to have a higher incidence (Ref)

• Age >50 years (Ref)

• BMI >25 kg/m2 (Ref)

Malignancy

In general, the chronic use of immunosuppression agents (including azathioprine) increases the risk of lymphoproliferative disorders and/or neoplasms (including skin carcinoma). Malignancies reported have included malignant lymphoma, hepatosplenic T-cell lymphoma (HSTCL), hemophagocytic lymphohistiocytosis (HLH), acute myelocytic leukemia, myelodysplastic syndrome, and malignant neoplasm of skin, among others (Ref). HSTCL and HLH are especially of concern in patients with inflammatory bowel disease (IBD) and the risk is further increased with use of thiopurines (Ref); HSTCL has also been reported in solid organ transplant recipients receiving azathioprine (Ref).

The risk of skin cancer in comparison to other immunosuppressants is unclear (Ref). There is some evidence that risk of developing nonmelanoma skin cancers returns to baseline in patients with IBD who discontinue use of azathioprine; however, further study is required (Ref).

Mechanism: Dose- and time-related; related to the pharmacologic action. Azathioprine metabolites are incorporated into replicating DNA and halt replication, including in lymphocytes; azathioprine also blocks the pathway for purine synthesis (Ref). A decrease in the ability to repair UV-induced DNA lesions may contribute to risk of skin cancer (Ref). Azathioprine and its metabolites may also be direct inhibitors of cytotoxic T cell and natural killer cell function (Ref).

Onset: Delayed. Post-transplant lymphoproliferative disorders (PTLD) and non-skin-non-lymphoma malignancies generally occur during the first year after transplant when immunosuppressive therapy is most aggressive; however, the incidence of skin malignancies increase more linearly with time (Ref).

Risk factors:

• Intensity and duration of immunosuppression (Ref)

• Concomitant use of other immunosuppressive agents or preexisting immune function impairment

• Epstein-Barr virus (EBV) seronegative transplant recipients (Ref)

- Note: In general, pediatric transplant recipients are at a higher risk of PTLD as these patients are more likely to be EBV seronegative at transplantation (Ref)

- Note: Clinicians may also consider the role that EBV acute infection and/or reactivation may play in the risk of EBV-associated lymphoma in patients receiving immunosuppressive therapies for any indication; risk not well defined (Ref)

• Pretransplant malignancy (Ref)

• Fewer HLA matches (Ref)

• History of at least 1 prior rejection episode (Ref)

• Age <25 years or >50 years (Ref)

HSTCL:

- Young age (between 10 and 35 years) (Ref)

- Males (Ref)

- History of inflammatory bowel disease (Ref)

- Concomitant use of tumor necrosis factor-α (TNF-α) inhibitors (Ref)

HLH:

- History of inflammatory bowel disease (Ref)

- Viral infection, primarily EBV infection (Ref)

- Note: Several other bacterial, fungal, or parasitic coinfections (eg, Mycobacterium tuberculosis, histoplasmosis, HIV, cytomegalovirus) have been associated with secondary HLH (Ref)

Skin carcinoma: Exposure to sunlight/UV light

Pancreatitis

Acute pancreatitis may occur in adult and pediatric patients receiving azathioprine (Ref). Cases are generally mild and reversible upon discontinuation (Ref); however, severe disease may occur (Ref). Azathioprine-related pancreatitis associated with polyarthralgia and panniculitis (PPP syndrome) has also been reported (Ref).

Mechanism: Non–dose-related; idiosyncratic (Ref)

Onset: Varied; in one trial, patients were diagnosed with acute pancreatitis after a median of 21 days of azathioprine therapy (range: 7 to 63 days) (Ref). Most cases were identified within 90 days of treatment initiation in pediatric patients receiving azathioprine for inflammatory bowel disease (Ref).

Risk factors:

• Smoking (Ref)

• Concomitant use of oral budesonide (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency dependent upon dose, duration, indication, and concomitant therapy.

>10%:

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

Hematologic & oncologic: Leukopenia (dose dependent; renal transplant: >50%; rheumatoid arthritis: 28%)

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

1% to 10%: Hematologic & oncologic: Neoplasm (excluding lymphoma; renal transplant: 3%)

<1%: Hematologic & oncologic: Malignant lymphoma

Frequency not defined:

Dermatologic: Alopecia, skin rash, Sweet's syndrome (acute febrile neutrophilic dermatosis)

Endocrine & metabolic: Negative nitrogen balance

Gastrointestinal: Diarrhea, steatorrhea

Hematologic & oncologic: Bone marrow depression, malignant neoplasm of skin, thrombocytopenia (dose-dependent)

Neuromuscular & skeletal: Arthralgia

Respiratory: Interstitial pneumonitis (reversible)

Miscellaneous: Fever

Postmarketing:

Dermatologic: Erythema nodosum (González-Olivares 2017)

Gastrointestinal: Cholestasis (Gisi 2019), gastrointestinal hypersensitivity (Riedel 1990), pancreatitis (including pancreatitis polyarthritis panniculitis [PPP] syndrome) (Mishra 2020, Teich 2016)

Hematologic & oncologic: Acute myelocytic leukemia (Yenson 2008), anemia, aplastic anemia (Yeter 2013), hemophagocytic lymphohistiocytosis (Biank 2011), hemorrhage (Perri 2007), hepatosplenic T-cell lymphomas (Carvão 2019), macrocytic anemia (Zazgornik 1997), malignant solid tumor, NK cell deficiency (Orandi 2007), pancytopenia (Jensen 2018)

Hepatic: Hepatic sinusoidal obstruction syndrome (formerly known as hepatic veno-occlusive disease) (Lemley 1989) hepatotoxicity (idiosyncratic) (Chalasani 2021; Romagnuolo 1998)

Hypersensitivity: Drug-induced hypersensitivity reaction (McKenzie 2021)

Infection: JC virus infection (Pagnoux 2003)

Nervous system: Progressive multifocal leukoencephalopathy (Pagnoux 2003)

Respiratory: Hypersensitivity pneumonitis (Lee 2016)

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

Warnings/Precautions

Disease-related concerns:

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

• Renal impairment: Use with caution in patients with renal impairment.

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).

Warnings: Additional Pediatric Considerations

The development of secondary hemophagocytic lymphohistiocytosis (HLH), a rare and frequently fatal activation of macrophages which causes phagocytosis of all bone marrow blood cell lines, is increased (100-fold) in pediatric patients diagnosed with inflammatory bowel disease due to chronic inflammation; this risk is further increased with concomitant thiopurine (ie, azathioprine or mercaptopurine) therapy, Epstein-Barr virus, or possibly other infections; if patient on thiopurine therapy presents with fever for at least 5 days, cervical lymphadenopathy, and lymphopenia, discontinue immunosuppressive therapy and further diagnostic evaluation for HLH should be performed; delay in diagnosis has been associated with increased mortality (Biank, 2011).

Metabolism/Transport Effects

None known.

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. Risk C: Monitor therapy

Abrocitinib: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

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. Risk D: Consider therapy modification

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

Baricitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Baricitinib. Risk X: Avoid combination

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

BCG Products: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of BCG Products. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of BCG Products. Risk X: Avoid combination

Brincidofovir: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Brincidofovir. Risk C: Monitor therapy

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

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

Cladribine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Cladribine. Risk X: Avoid combination

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

Coccidioides immitis Skin Test: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the diagnostic effect of Coccidioides immitis Skin Test. Management: Consider discontinuing therapeutic immunosuppressants several weeks prior to coccidioides immitis skin antigen testing to increase the likelihood of accurate diagnostic results. Risk D: Consider therapy modification

COVID-19 Vaccine (Adenovirus Vector): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Adenovirus Vector). Risk C: Monitor therapy

COVID-19 Vaccine (Inactivated Virus): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Inactivated Virus). Risk C: Monitor therapy

COVID-19 Vaccine (mRNA): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (mRNA). Management: Consider administration of a 3rd dose of COVID-19 vaccine, at least 28 days after completion of the primary 2-dose series, in patients 5 years of age and older taking immunosuppressive therapies. Risk D: Consider therapy modification

COVID-19 Vaccine (Subunit): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of COVID-19 Vaccine (Subunit). Risk C: Monitor therapy

Cyclophosphamide: AzaTHIOprine may enhance the hepatotoxic effect of Cyclophosphamide. Risk C: 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. Risk D: Consider therapy modification

Dengue Tetravalent Vaccine (Live): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Dengue Tetravalent Vaccine (Live). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Dengue Tetravalent Vaccine (Live). Risk X: Avoid combination

Denosumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Denosumab. Management: Consider the risk of serious infections versus the potential benefits of coadministration of denosumab and immunosuppressants. If combined, monitor for signs/symptoms of serious infections. Risk D: Consider therapy modification

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

Echinacea: May diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Management: Consider avoiding echinacea in patients receiving therapeutic immunosuppressants. If coadministered, monitor for reduced efficacy of the immunosuppressant during concomitant use. Risk D: Consider therapy modification

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

Fexinidazole: Myelosuppressive Agents may enhance the myelosuppressive effect of Fexinidazole. Risk X: Avoid combination

Inebilizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Inebilizumab. Risk C: 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. Risk C: Monitor therapy

Influenza Virus Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Influenza Virus Vaccines. Management: Administer influenza vaccines at least 2 weeks prior to initiating immunosuppressants if possible. If vaccination occurs less than 2 weeks prior to or during therapy, revaccinate 2 to 3 months after therapy discontinued if immune competence restored. Risk D: Consider therapy modification

Leflunomide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Leflunomide. Management: Increase the frequency of chronic monitoring of platelet, white blood cell count, and hemoglobin or hematocrit to monthly, instead of every 6 to 8 weeks, if leflunomide is coadministered with immunosuppressive agents. Risk D: Consider therapy modification

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

Natalizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Natalizumab. Risk X: Avoid combination

Ocrelizumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ocrelizumab. Risk C: Monitor therapy

Ofatumumab: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ofatumumab. Risk C: Monitor therapy

Pidotimod: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Pidotimod. Risk C: Monitor therapy

Pimecrolimus: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Pimecrolimus. Risk X: Avoid combination

Poliovirus Vaccine (Live/Trivalent/Oral): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Poliovirus Vaccine (Live/Trivalent/Oral). Risk X: Avoid combination

Polymethylmethacrylate: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the potential for allergic or hypersensitivity reactions to Polymethylmethacrylate. Management: Use caution when considering use of bovine collagen-containing implants such as the polymethylmethacrylate-based Bellafill brand implant in patients who are receiving immunosuppressants. Consider use of additional skin tests prior to administration. Risk D: Consider therapy modification

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

Rabies Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rabies Vaccine. Management: Complete rabies vaccination at least 2 weeks before initiation of immunosuppressant therapy if possible. If post-exposure rabies vaccination is required during immunosuppressant therapy, administer a 5th dose of vaccine and check for rabies antibodies. Risk D: Consider therapy modification

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. Risk D: 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. Risk D: Consider therapy modification

Ropeginterferon Alfa-2b: Myelosuppressive Agents may enhance the myelosuppressive effect of Ropeginterferon Alfa-2b. Management: Avoid coadministration of ropeginterferon alfa-2b and other myelosuppressive agents. If this combination cannot be avoided, monitor patients for excessive myelosuppressive effects. Risk D: Consider therapy modification

Rubella- or Varicella-Containing Live Vaccines: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Rubella- or Varicella-Containing Live Vaccines. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Rubella- or Varicella-Containing Live Vaccines. Risk X: Avoid combination

Ruxolitinib (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Ruxolitinib (Topical). Risk X: Avoid combination

Sipuleucel-T: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Sipuleucel-T. Management: Consider reducing the dose or discontinuing the use of immunosuppressants prior to initiating sipuleucel-T therapy. Risk D: Consider therapy modification

Sphingosine 1-Phosphate (S1P) Receptor Modulator: May enhance the immunosuppressive effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk C: Monitor therapy

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

Tacrolimus (Topical): Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tacrolimus (Topical). Risk X: Avoid combination

Talimogene Laherparepvec: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Talimogene Laherparepvec. Specifically, the risk of infection from the live, attenuated herpes simplex virus contained in talimogene laherparepvec may be increased. Risk X: Avoid combination

Tertomotide: Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Tertomotide. Risk X: Avoid combination

Tofacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Tofacitinib. Management: Coadministration of tofacitinib with potent immunosuppressants is not recommended. Use with non-biologic disease-modifying antirheumatic drugs (DMARDs) was permitted in psoriatic arthritis clinical trials. Risk X: Avoid combination

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

Typhoid Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Typhoid Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Typhoid Vaccine. Risk X: Avoid combination

Upadacitinib: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the immunosuppressive effect of Upadacitinib. Risk X: Avoid combination

Vaccines (Inactivated): Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Vaccines (Inactivated). Management: Give inactivated vaccines at least 2 weeks prior to initiation of immunosuppressants when possible. Patients vaccinated less than 14 days before initiating or during therapy should be revaccinated at least 2 to 3 months after therapy is complete. Risk D: Consider therapy modification

Vaccines (Live): May enhance the adverse/toxic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Specifically, the risk of vaccine-associated infection may be increased. Vaccines (Live) may diminish the therapeutic effect of Immunosuppressants (Therapeutic Immunosuppressant Agents). Risk X: Avoid combination

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

Yellow Fever Vaccine: Immunosuppressants (Therapeutic Immunosuppressant Agents) may enhance the adverse/toxic effect of Yellow Fever Vaccine. Specifically, the risk of vaccine-associated infection may be increased. Immunosuppressants (Therapeutic Immunosuppressant Agents) may diminish the therapeutic effect of Yellow Fever Vaccine. Risk X: Avoid combination

Reproductive Considerations

The manufacturer recommends that patients 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 may also be acceptable for use in patients with rheumatic and musculoskeletal diseases who are planning to become pregnant. Conception should be planned during a period of quiescent/low disease activity (ACR [Sammaritano 2020]).

Patients with autoimmune hepatitis who are planning to become pregnant 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 patients with rheumatic and musculoskeletal diseases who are planning to father a child (ACR [Sammaritano 2020]).

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.

Although use for rheumatoid arthritis in pregnant patients is contraindicated by the manufacturer, available guidelines suggest that use of azathioprine may be acceptable for the management of rheumatic and musculoskeletal diseases during pregnancy (ACR [Sammaritano 2020]).

Patients 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 patient refractory to preferred agents (Provan 2019). 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.

Breastfeeding Considerations

The azathioprine metabolite 6-mercaptopurine (6-MP) is present in breast milk.

Azathioprine is a prodrug which is rapidly metabolized to 6-MP. 6-MP is present in breast milk; however, it is inactive until further metabolized to 6-TGN metabolites which are present only within red blood cells (Christensen 2008; Mottet 2016).

Peak breast milk concentrations of 6-MP occurred within 4 hours in a study of eight lactating women (Christensen 2008). Another study measured the active metabolite concentrations in RBCs of four breastfeeding women ≥3 months' postpartum on chronic azathioprine therapy; sampling was conducted at variable times after the dose. Women in the study had normal thiopurine methyltransferase (TPMT) activity. All women had therapeutic concentrations of 6-TGN; however, none of the infants had detectable concentrations (Gardiner 2006). Newborn serum concentrations of 6-MP and 6-TGN were also undetectable in a study which evaluated seven breastfed infants between 1 and 28 days' postpartum. Mothers in this study were taking azathioprine 100 mg/day (Sau 2007).

Information is available from a report of 29 women taking azathioprine 50 to 175 mg/day throughout pregnancy and postpartum and their 30 breastfed newborns. Among 20 infants with blood cell counts evaluated after delivery, one infant was diagnosed with asymptomatic neutropenia on day 15 of life. Neutropenia fluctuated over 1.5 months of breastfeeding, continued for 15 days after breastfeeding was discontinued, and resolved 3.5 months later. No adverse outcomes were observed in the remaining infants who were followed for 1 to 17 months (Bernard 2013). A second study of 11 women taking azathioprine maintenance doses for inflammatory bowel disease (median: 150 mg/day) did not find an increased risk of infection in their 15 breastfed infants. The infants were followed for 6 months to 6 years (Angelberger 2011).

Recommendations for breastfeeding during azathioprine therapy vary. Due to the potential for serious adverse reactions in the infant, breastfeeding is not recommended by the manufacturer. The World Health Organization also recommends breastfeeding be avoided during maternal treatment (WHO 2002).

Recommendations for breastfeeding in females taking azathioprine following a kidney transplant differ; generally breastfeeding may be considered with maternal use of maintenance doses (Constantinescu 2014; EBPG 2002; KDIGO 2009; López 2014). Azathioprine is considered compatible for use in women with inflammatory bowel disease who wish to breastfeed (AGA [Mahadevan 2019]). Azathioprine may be continued or initiated in patients with rheumatic and musculoskeletal diseases who are breastfeeding (ACR [Sammaritano 2020]).

Patients who are concerned with the theoretical risks of immunosuppression may consider pumping and discarding breast milk for the first 4 hours after an azathioprine dose to decrease potential exposure to the breastfed infant (ACR [Sammaritano 2020; Christensen 2008). Monitoring infant blood cell count 10 to 15 days after breastfeeding is initiated or in infants with frequent infections may also be considered (ACR [Sammaritano 2020]; Bernard 2013).

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 or as clinically indicated), total bilirubin, LFTs (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 (CPIC [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 (CPIC [Relling 2019]).

TPMT and NUDT15 testing cannot substitute for monitoring CBC in patients receiving azathioprine.

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).

Mechanism of Action

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.

Pharmacokinetics

Onset of action: Immune thrombocytopenia (oral): Initial response: 30 to 90 days; Peak response: 30 to 120 days (ASH [Neunert 2011]).

Absorption: Oral: Well absorbed.

Protein binding: ~30%.

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).

Half-life elimination: Azathioprine and mercaptopurine: Variable: ~2 hours (Taylor 2005).

Time to peak: Oral: 1 to 2 hours (including metabolites).

Excretion: Urine (primarily as metabolites).

Pharmacokinetics: Additional Considerations

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).

Pricing: US

Solution (reconstituted) (azaTHIOprine Sodium Injection)

100 mg (per each): $300.00

Tablets (Azasan Oral)

75 mg (per each): $24.83

100 mg (per each): $11.07

Tablets (azaTHIOprine Oral)

50 mg (per each): $2.10 - $6.81

75 mg (per each): $20.71

100 mg (per each): $9.23

Tablets (Imuran Oral)

50 mg (per each): $9.59

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Aza-Q (DE);
  • Azadus (TH);
  • Azafalk (DE);
  • Azafrine (KR);
  • Azamun (AE, MY, NZ, SA, TW);
  • Azamune (GB);
  • Azanin (JP);
  • Azapin (AU);
  • Azapress (ZA, ZW);
  • Azaprin (AE, KW, SA);
  • Azaprine (KR);
  • Azarekhexal (EE);
  • Azarex (DE);
  • Azarin (EG);
  • Azathiodura (DE);
  • Azatioprina (PE);
  • Azatioprina Wellcome (IT);
  • Azatrilem (MX);
  • Azoran (IN);
  • Azostal (LK);
  • Colinsan (DE);
  • Imazan (AU);
  • Immuthera (KR);
  • Imuger (IE);
  • Imunen (BR);
  • Imuprin (AE, BB, BF, BH, BJ, BM, BS, BZ, CI, CY, ET, FI, GH, GM, GN, GY, HK, IQ, IR, JM, JO, KE, KW, LR, LY, MA, ML, MR, MT, MU, MW, NE, NG, OM, PR, SA, SC, SD, SL, SN, SR, SY, TH, TN, TT, TW, TZ, UG, YE, ZM, ZW);
  • Imuprine (NZ);
  • Imuran (AE, AR, AU, BB, BD, BE, BF, BG, BH, BJ, BM, BS, BZ, CI, CL, CN, CO, CY, CZ, EC, EE, EG, ET, GB, GH, GM, GN, GR, GY, HK, HN, HR, HU, ID, IE, IL, IN, IQ, IR, JM, JO, JP, KE, KR, KW, LB, LR, LT, LU, LV, LY, MA, ML, MR, MU, MW, MX, MY, NE, NG, NL, NZ, OM, PH, PK, PL, PT, PY, QA, RO, RU, SA, SC, SD, SG, SI, SK, SL, SN, SR, SY, TH, TN, TR, TT, TW, TZ, UG, UY, VN, YE, ZM, ZW);
  • Imurek (AT, CH, DE);
  • Imurel (DK, ES, FI, FR, IS, NO, SE, VN);
  • Renzat (PH);
  • Thioprine (AU);
  • Transimune (IN);
  • Zaprine (ZA);
  • Zytrim (DE)


For country abbreviations used in Lexicomp (show table)

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